BIOPHARMACEUTICS

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Course Specifications
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Professional Information
1. Overall aims of the course
Upon successful completion of this course, the students should be able to:
- Outline the factors affecting oral drug bioavailability.
- Point out the absorption mechanisms and the factors affecting them.
- Review the role of food and formulation design in modifying the drug absorption,
distribution and elimination.
- Identify the factors affecting drug distribution, metabolism and elimination.
2. Intended learning outcomes of the course (ILOs)

a- Knowledge and understanding:
On successful completion of the course, the graduate should be able to:
 a1- Describe the mechanisms of gastrointestinal absorption of drugs.
 a2- Discuss the factors affecting gastrointestinal absorption of drugs.
 a3- Identify the role of dosage form on drug bioavailability.
 a4-Enumerate the factors affecting drug distribution, metabolism and
elimination.
 a5- Define bioavailability and bioequivalance.
b- Intellectual skills
 b1- Suggest the dosage regimen.
 b2-Comprehend the biopharmaceutical considerations in drug product design.
 b3-Recognize the relationship between product design and the drug
absorption, distribution and elimination.
 b4- Predict the effect of excipients and food on drug absorption, distribution
and elimination.
c- Professional and practical skills

 c1- Handle the results of the in-vitro and in-vivo studies.
 c2-Assess physicochemical characteristics of drug substances as a factor
affecting drug absorption.
 c3- Conduct bioavailability and bioequivalence studies.
 c4- Apply the biopharmaceutical consideration in dosage form design.
Course Specifications
d- General and transferable skills

 d1- Work independently and in groups.
 d2- Retrieve and evaluate information from different sources.
3. Teaching and learning methods

a. Lectures
b. Practical training / laboratory
c. Seminar / Workshop
d. Class Activity
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BIOPHARMACEUTICS
Definitions
 Biopharmaceutics: is the study of the relationship
between the physicochemical properties of the
drug [active pharmaceutical ingredients, (API)]
and the drug product (dosage form in which the
drug is fabricated) and the biological performance
of the drug
 Bioavailability: is the rate and extent of systemic

drug absorption
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Definitions
Pharmacokinetics: is the study of the time
course and fate of drugs in the body.
Pharmacokinetics involves the kinetics of drug

absorption, distribution, and elimination
(metabolism and excretion) (ADME).
 The description of drug distribution and elimination

is often termed drug disposition
Definitions
 Pharmacodynamics: is the study of
the relation of the drug concentration
at the site of action and its
pharmacologic response.
 Systemic circulation is the venous
blood (excluding hepatic portal
blood during the absorption
phase) and arterial blood.
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Hepatic portal blood during the

absorption phase
LADME System
Itis the factors affecting drug concentration
in blood plasma that refer to:
L ( Liberation),
A (Absorption),
D (Distribution),
M (Metabolism)
E (Excretion)
Elimination = metabolism and excretion
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The dynamic relationships among the

drug, the drug product, and the
pharmacological effect
LADME
 Input processes are:
 L = Liberation, the release of the drug from it’s dosage form.
 A = Absorption, the movement of the drug from the site of
administration to the blood circulation. The term commonly used to
describe the rate and extent of the drug input is bioavailability. Drugs
administered by intravenous routes exhibit essentially 100%
bioavailability
 Output processes, or disposition of the drug are:
 D = Distribution, the process by which drug diffuses or is transferred
from intravascular space to extravascular space (body tissues).
 M = Metabolism, the chemical conversion or transformation of drugs
into compounds which are easier to eliminate.
 E = Excretion, the elimination of unchanged drug or metabolite from
the body via renal, biliary, or pulmonary
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Pharmacokinetics Pharmacodynamics
Pharmacokinetics describes the

time course of drug
Pharmacodynamics describes
concentration in one or more the time course and the
biological specimen, normally magnitude of the
plasma, serum, or whole blood, pharmacological response of
which reflects several processes the drugs.
including absorption, Based on the classic receptor-
distribution, metabolism and occupancy theory, after drug
elimination
molecules reach the target
biophase, it binds to the
receptors to form the drug-
receptor complex to exert
pharmacological response
What does the body do to the What does the drug do to the
drug? body?
Fate of Drug in the Body

 Once the drug is systemically absorbed, normal
physiologic processes for distribution and
elimination occur, which usually is not influenced by
the specific formulation of the drug.
 The rate of drug release from the product, and the

rate of drug absorption, is important in determining
the onset, intensity, and duration of drug action.
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Generalized plasma level-time curve

after oral administration of a drug
(pharmacological parameters)
Rate-limiting Steps In Oral Drug Absorption
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Rate-limiting Steps In Oral Drug

Absorption
 Systemic drug absorption from a drug product
consists of succession of the rate processes.
 For solid oral, immediate release drug products
(e.g., tablets, capsule), the rate processes include:
 1. Disintegration of the drug product and subsequent
release of the drug;
 2. Dissolution of the drug in an aqueous
environment; and
 3. Absorption across cell membranes into the
systemic circulation
RATE-LIMITING STEPS IN ORAL

DRUG ABSORPTION
 In the process of drug disintegration, dissolution,
and absorption, the rate at which drug reaches the
circulatory system is determined by the slowest
step in the sequence
 The slowest step in a kinetic process is the rate
limiting step.
 Except for controlled release products,
disintegration of a solid oral drug product is
usually more rapid than drug dissolution and drug
absorption.
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RATE-LIMITING STEPS IN ORAL

DRUG ABSORPTION
 For drugs that have very poor aqueous
solubility, the rate at which the drug dissolves
(dissolution) is often the slowest step, and
therefore exerts a rate-limiting effect on drug
bioavailability.
 In contrast, for a drug that has a high aqueous
solubility, the dissolution rate is rapid and the
rate at which the drug crosses or permeates cell
membranes is the slowest or rate-limiting step.
Drug Absorption
 For systemic absorption, a drug must pass from
the absorption site through or around one or
more layers of cells to gain access into the
general circulation
 The permeability of a drug at the absorption site
into the systemic circulation is intimately related
to the molecular structure of the drug and the
physical and biochemical properties of the cell
membrane
 Membrane is the major structure in the cell, so
drug must traverse the cell membrane for
absorption into the cell.
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Schematic diagram showing the cells, cell

membranes, intracellular and extracellular fluids,
and the blood in the capillaries
Oral Drug Absorption

An orally administered drug must pass
through a number of membranes in order to
be absorbed into the systemic circulation
Many physiological membranes differ in
structure and function
Despite this, there is general consensus
regarding the basic structure of the cell
membrane
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The Cell Membrane

 The primary structure of the cell membrane is a 5-
nm thick bimolecular lipid film that separates
intracellular and extracellular fluids.
 The lipid is composed mainly of the phospholipids,
phosphatidylserine and phosphatidylinositol, and
contains saturated and unsaturated fatty acids and
sterols
 The bilayer exhibits high permeability to
hydrophobic molecules and low permeability to
hydrophilic molecules.
The Cell Membrane

 The cell membrane is associated with intrinsic
and extrinsic proteins.
 Intrinsic proteins are globular proteins that
generally span the bilayer and are held within
the membrane by hydrophobic and electrostatic
interactions.
 The proteins can form channels, carriers, or
pumps that enable polar molecules to cross the
membranes.
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Structure of Cell Membrane
Structure of Cell Membrane
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Intestinal Membrane
Passage of Drugs across Cell

Membranes
 For absorption into the cell, a drug must traverse
the cell membrane.
 Transcellular absorption is the process of a drug
movement across the cell.
 Some polar molecules may not be able to traverse
the cell membrane, but instead, go through gaps or
"tight junctions" between cells, a process known as
paracellular drug adsorption
 Some drugs are probably absorbed by a mixed
mechanism involving one or more processes
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Drug transport and site of action
Types of Intestinal Membrane

Transport
Intestinal membrane transport include
paracellular and transcellular transport.
Transcellular transport can be further divided
into passive diffusion, endocytosis, and
carrier-mediated transport
Paracellular transport refers to the passage of
solute without passage through the epithelium
cells
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1- Passive Diffusion
This mechanism is based primarily on liquid
solubility and concentration gradient.
It is responsible for membrane transport of
the great majority of drugs.
Passive diffusion is the process by which
molecules spontaneously diffuse from a
region of higher concentration to a region of
lower concentration
Follow; 1- Passive Diffusion

This process is passive because no external
energy is expended
The direction of mass transfer of molecules
or substances by passive diffusion depends
on the concentration gradient on the two
sides of the membrane (the driving force for
passive diffusion)
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Passive Diffusion of molecules

 Molecules in solution
diffuse randomly in all
directions
 As molecules diffuse from
left to right and vice versa
(small arrows), a net
diffusion from the high-
concentration side to the
low-concentration side
results.
 This results in a net flux (J)
to the right side.

The transport of drug molecules occurs until
equilibrium.
This equilibrium is not attained in vivo and the
drug quantitatively absorbed.
This is because drug distributes rapidly into a
large volume after entering the blood resulting
in a very low plasma drug concentration with
respect to the concentration at the site of drug
administration.
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 Drug is usually given in milligram doses,
whereas plasma drug concentrations are
often in the microgram per milliliter or
nanogram per milliliter range.
 For drugs given orally, CGI> CP.
A large concentration gradient is maintained
driving drug molecules into the plasma from
the GI tract
Passive Diffusion
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According to Fick’s Law of Diffusion,

drug molecules diffuse from a region of
high drug concentration to a region of
low drug concentration
Fick’s Law
 dQ/dt ={DAK/h}(CGI – Cp)
 Where dQ/dt = rate of diffusion; D = diffusion

coefficient; K = partition coefficient; A = surface
area of the membrane; h = membrane thickness;
and CGI – Cp = difference between the
concentrations of drug in the GI tract and in the
plasma.
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Factors affecting passive diffusion

1- partition coefficient of the drug
 The partition coefficient, K, represents the lipid-
water partitioning of a drug
 Typically, hydrophobic molecules have high
partition coefficients, while hydrophilic
molecules have low partition coefficients.
 More lipid soluble drugs have larger K values
that theoretically increase the rate of systemic
drug absorption
 In practice, drug absorption is influenced by
other physical factors of the drug, limiting its
practical application of K.

2- The surface area of the membrane
 The surface area of the membrane through which the
drug is absorbed directly influences the rate of drug
absorption.
 Drugs may be absorbed from most areas of the GI
tract
 However, the duodenal area of the small intestine
shows the most rapid drug absorption due to such
anatomic features as villi and microvilli, which
provide a large surface area.
 These villi are not found in such numbers in other
areas of the GI tract.
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3- The membrane thickness
 The membrane thickness, h, is a constant at the
absorption site but may be altered by disease.
 Drugs usually diffuse very rapidly into tissues through
capillary cell membranes in the vascular
compartments.
 In the brain, the capillaries are densely lined with glial
cells creating a thicker lipid barrier (blood-brain
barrier) causing a drug to diffuse more slowly into
brain
 In certain disease states (e.g., meningitis) the cell
membranes may be disrupted or become more
permeable to drug diffusion.

4- Diffusion coefficient (D)
The value of D depends on the size of the
molecule and the viscosity of the dissolution
medium.
Increasing the viscosity will decrease the
diffusion coefficient and thus the dissolution
rate.
This could be used to produce a sustained
release effect by including a larger proportion
of something like sucrose or acacia in a tablet
formulation.
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5- The degree of ionization
Drugs may be classified into three
categories:
1-Strong electrolytes: ex. K+, Cl – or NH4 +
2-Non- electrolyte: ex. Sugars and steroids
3-Weak electrolytes: weak acids and weak
bases
For weak electrolyte drugs (i.e., weak acids,
bases), the extent of ionization influences
drug solubility and the rate of drug transport.

Follow; 5- The degree of ionization
 Molecules that are weak acids or bases cross
membranes more rapidly when they are in the non-
ionized form.
 However, aqueous solubility is favored for the
ionized form.
 In order to be available to cross any membrane, a
drug must be in solution.
 This paradoxical requirement of both aqueous and
lipid solubility is of particular concern in the area of
drug absorption and presents a constant challenge in
pharmaceutical formulation.
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 Ionized drugs are more water soluble than non-
ionized drugs which are more lipid soluble.
 The extent of ionization of a weak electrolyte
depends on the pKa of the drug and the (pH) of
the medium in which the drug is dissolved.
 The Henderson and Hasselbalch equation
describes the ratio of ionized (charged) to
unionized form of the drug and is dependent on
the pH of the medium and the pKa of the drug:

For weak acids:
HA + H2O H3O+ + A-
Ka = (A-) (H3O+) / (HA)
pH = pKa + Log (A-) / (HA)
For weak bases:
BH+ + H2O H3O+ + B
Ka = (B) (H3O+) / (BH+)
pH = pKa + Log (B) / (BH+)
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For an  Ka +
acid: HA H + A
[H+][A-] 100
Ka = % ionised =
[AH] 1 + 10(pKa - pH)
For a  Ka +
base: BH+ H + B
[H+][B] 100
Ka = % ionised =
[BH+] 1 + 10(pH - pKa)
When an acid or base is 50% ionised:

pH = pKa
pH – Partition Hypothesis
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pH – Partition Hypothesis
Describe the influence of GI pH and drug
pKa (the degree of ionization) on the
extent of drug transfer or drug absorption
The non-ionized form is the absorbable

form due to higher lipid solubility.
The ionized form is not able to get through

the lipid membrane.

6- The drug affinity for tissue component
 The drug concentration on either side of a
membrane is also influenced by the affinity of the
drug for a tissue component, which prevents the
drug from freely moving back across the cell
membrane
 For example, drug that binds plasma or tissue
proteins causes the drug to concentrate in that region
 Dicumarol and sulfonamides strongly bind plasma
proteins; whereas, chlordane, a lipid-soluble
insecticide, partitions and concentrates into adipose
(fat) tissue.
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Follow; 6- The drug affinity for tissue component
Tetracycline forms a complex with calcium
and concentrates in the bones and teeth.
Drugs may concentrate in a tissue due to a
specific uptake or active transport process.
Such processes have been demonstrated for
iodide in thyroid tissue, potassium in the
intracellular water, and certain
catecholamines in adrenergic storage sites.
Carrier-mediated transport
2.1- Active transport
2.2- Facilitated diffusion
2.3- Carrier-Mediated Intestinal

transport
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Hypothetical carrier – mediated

transport process.
2.1- Active transport

Active transport is a carrier mediated trans-
membrane process that is important for GI
absorption of some drugs and also involved
in the renal and biliary secretion of many
drugs and metabolites.
A carrier binds the drug to form a carrier-
drug complex that shuttles the drug across
the membrane and then dissociates the drug
on the other side of the membrane.
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Follow 2.1- Active transport

Active transport is an energy-consuming
system characterized by the transport of drug
against a concentration gradient, that is, from
regions of low drug concentrations to regions
of high concentrations.
A drug may be actively transported, if the
drug molecule structurally resembles a
natural substrate that is actively transported.
Follow 2.1- Active transport

A few lipid-insoluble drugs that resemble
natural physiologic metabolites (e.g., 5-
fluorouracil) are absorbed from the GI tract by
this process.
 Drugs of similar structure may compete for
adsorption sites on the carrier.
 Because only a certain amount of carrier is
available, the binding sites on the carrier may
become saturated at high drug concentrations.
 In contrast, passive diffusion is not saturable.
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Active Transport
2.2- Facilitated Diffusion

 Facilitated diffusion is a non-energy requiring,
carrier-mediated transport system in which the
drug moves along a concentration gradient (i.e.,
moves from a region of high drug concentration
to a region of low drug concentration).
 Facilitated diffusion is saturable, structurally
selective for the drug and shows competition
kinetics for drugs of similar structure.
 Facilitated diffusion seems to play a very minor
role in drug absorption (Vit.B12)
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Facilitated Diffusion
Carrier – Mediated Intestinal

Transport
 Various carrier mediated systems (transporters) are
present at the intestinal brush border and
basolateral membrane for the absorption of specific
ions and nutrients essential for the body.
 Many drugs are absorbed by these carriers because
of the structural similarity to natural substrates.
 An intestinal trans-membrane protein, p-
Glycoprotein (p-Gp) appears to reduce apparent
intestinal epithelial cell permeability from lumen to
blood for various lipophilic or cytotoxic drugs.
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Multiple pathways for intestinal

absorption of a compound
1) Passive transcellular
2) Active transcellular
3) Facilitated diffusion
4) Passive paracellular
5) Absorption limited by
P-gp and/or other efflux
transporters
6) Intestinal first-pass
metabolism followed by
absorption of parent and
metabolite
7) Receptor-mediated influx
transport.
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3- Vesicular transport
 Vesicular transport is the process of engulfing
particles or dissolved materials by the cell.
 Pinocytosis (cell drinking) refers to the engulfment
of small solutes or fluid.
 Phagocytosis (cell eating) refers to the engulfment
of larger particles or macromolecules generally by
macrophages.
 Endocytosis and exocytosis are the processes of
moving macromolecules into and out of a cell,
respectively.
Follow; 3- Vesicular transport

 During pinocytosis or phagocytosis, the cell
membrane invaginates to surround the material,
and then engulfs the material into cell.
 Subsequently, the cell membrane containing the
material forms a vesicle or vacuole within the
cell.
 Vesicular transport is the proposed process for
the absorption of orally administered sabin
polio vaccine and various large proteins
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Pinocytosis
Phagocytosis
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4- Paracellular transport
 Paracellular transport refers to transport solutes in
between cells, without passage through the epithelial
cells themselves.
 It is now well recognized that the intercellular
junctions between epithelial cells of capillaries are
“leaky,” allowing paracellular transport of small
molecules.
 Paracellular transport is passive transport, follows
drug concentration gradients, and does not require
energy.
 In the intestine, molecules smaller than 500 MW may
be absorbed by paracellular drug absorption.
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Factors Affecting Oral Drug

Absorption
1- physicochemical 2- physiological Factors:
factors: 2.1- pH of GIT fluids
1.1- Lipophilicity 2.2- Surface area of GIT
1.2- Degree of Ionization absorption sites
1.3- Size 2.3- Gastric emptying rate.
1.4- Charge 2.4- Intestinal motility
1.5- Solubility and 2.5- Drug stability in the GIT
Dissolution 2.6- Hepatic metabolism
1.6- Complexation 2.7- Malabsorption
1.7- Adsorption 2.8- Food
1.8- Stability 3- Dosage form Factors
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1.1- Lipophilicity
 The lipid solubility or lipophilicity of drugs
is a prerequisite for transcellular diffusion
across the intestinal membrane.
 The lipophilicity of drug substances is
expressed as the apparent partition
coefficient or distribution coefficient (log P)
between n-octanol and an aqueous buffer
(pH 7.4), which is pH-dependent in the case
of ionizable compounds.
Follow; 1.1- Lipophilicity

 In general, compounds with low log P are
poorly absorbed, whereas compounds with
log P > 1 offer satisfactory absorption.
 It is important, however, that the drug
possess an optimum lipophilicity, as too low
or too high lipophilicity may result in less
than optimum oral bioavailability.
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Follow; 1.1- Lipophilicity

 The high lipophilicity (log P > 3.5) decreases
drug transport across the intestinal epithelial
cells and could be accounted for loss of in
vivo biological activity.
 The “cut-off” point of P value, that is, the P
value corresponding to an optimal trans-
epithelial passage of drugs, was found to be
around 3000 (log P= 3.5).
Barbiturates PC o/w % Absorbed
Barbitone 0.7 12
Phenobarbitone 4.8 20
Cyclobarbitone 14 24
Hexobarbitone 100 44
Thiopentone 500 100
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1.2- Degree of ionization

 The interrelationship between the degree of
ionization of a weak electrolyte drug (determined
by its pka and pH of the absorption site) and the
extent of drug absorption is embodied in pH-
partition hypothesis.
 According to Henderson – Hasselbach equation
and pH- partition hypothesis, weak acids are
mainly absorbed from the stomach and weak bases
are mainly absorbed from the small intestine.
 However, this is not the actual situation and there
are limitations of pH – Partition Hypothesis.
Limitations of pH partition hypothesis

1. The rate of intestinal absorption of weak acids
is often higher than its rate of gastric absorption
due to:
 Larger mucosal surface area available for
drug absorption due to presence of villi and
microvilli
 Presence of an affective pH at the surface of
intestinal mucosa (virtual membrane pH) of
about 5.3 which is lower than the bulk lumen
pH (6.8- 7.5)
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Follow; Limitations of pH partition

hypothesis
2. A number of drugs are poorly absorbed from
certain areas of the gastrointestinal tract despite the
fact that their unionized forms predominate in such
area:
 Barbitone (pka= 7.8) which is totally unionized at
gastric pH (1.5- 3), is only poorly absorbed from the
stomach. However, Thiopentone which has a similar
pka (7.6) is much better absorbed from the stomach
than barbitone.
 This is because the lipid solubility of unionized form
of thiopentone is more than that of barbitone.
Follow; Limitations of pH partition

hypothesis
3. A number of drugs are absorbed
readily despite being ionized over the
entire pH range (1.5 – 8) of the GIT.
 This could be explained by the fact that
these drugs are absorbed by other
transport mechanisms (e.g. carrier
mediated transport)
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1.3- Size
 Passive absorption in the gastrointestinal tract is
severely limited by the size of the penetrating drug
molecule.
 This is probably due to the well-organized and
packed structure of the cell membrane lipid bilayer.
 When a molecule is too large, the potential energy
resulting from its concentration difference is not
large enough to generate the high energy required
to greatly disturb the bilayer
Follow; 1.3- Size

 Therefore, size and perhaps the
surface area of a molecule are major
factors that limit absorption via
passive diffusion.
 The optimal molecular weight is less
than 500 and may extend to 550.
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1.4- Charge
 Effects of charge on passive absorption of drugs are
well recognized.
 In general, charged molecules are not as permeable
as the corresponding uncharged species when the
compound is absorbed via passive diffusion.
 However, the effect of charge on the absorption of
drugs via a carrier-mediated transport process is not
simple.
 Some transporters favor neutral substrates, some
positively charged, and others negatively charged.
1.5- Solubility and Dissolution

 Solubility is the maximum amount of solute that dissolves
in a given quantity of solvent at a specific temperature to
form a saturated state (equilibrium solubility).
 Solubility affects the absorption of drugs because it affect
the driving force of drug absorption (the concentration of
drug molecules at the site of absorption).
 The drug dissolution rate is the amount of drug substance
that goes in solution per unit time under standardized
conditions of liquid/solid interface, temperature and
solvent composition.
 In biologic systems, drug dissolution in an aqueous
medium is an important prior condition of systemic
absorption.
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Dissolution
 The overall rate of drug dissolution may be
described by the Noyes-Whitney equation
which models dissolution of spherical drug
particles, when dissolution is diffusion
controlled and involves no chemical
reaction.
 Where, dC/dt = rate of drug dissolution,

 D = diffusion rate constant,
 A = surface area of the particle,
 Cs = drug concentration in the stagnant
layer,
 Cx = drug concentration in the bulk solvent,
and
 h = thickness of the stagnant layer.
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Follow; 1.5- Solubility and Dissolution
 As the drug particle dissolves, a

saturated solution (stagnant layer) is
formed at the immediate surface around
the particle.
 The dissolved drug in the saturated
solution gradually diffuses to the
surrounding regions.
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1- Physiological factors affecting

drug dissolution
1.1 Viscosity of GIT fluids
 The value of D depends on the size of the molecule
and the viscosity of the dissolution medium.
 Increasing the viscosity will decrease the diffusion
coefficient and thus the dissolution rate.
 This could be used to produce a sustained release
effect by including a larger proportion of something
like sucrose or acacia in a tablet formulation.
 The presence of food may decrease the rate of drug
dissolution by reducing the rate of diffusion of drug
molecules away from the diffusion layer.

drug dissolution
1.2- Degree of agitation
 Affect the thickness of the diffusion layer (h)
exhibited by each drug particles.
 Hence, an increase in gastric and/or
intestinal motility may increase the
dissolution rate of a sparingly soluble drug
by decreasing h
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drug dissolution
1.3- Rate of absorption
 Affect the concentration ( Cx) of drug in the bulk of
the gastrointestinal fluids.
 The increased rate of removal of dissolved drug
from bulk solution by absorption through GIT
resulted in decreased C x and enhanced dissolution.
 If Cx is much smaller than Cs then we have the so-
called “sink condition” and the equation is reduced
to:
Rate of Solution = D*A*Cs/h

drug dissolution
1.4- Volume of GIT fluids
 Affect the concentration ( Cx) of drug in
the bulk of the gastrointestinal fluids.
 In the stomach, the volume of fluids
will be influenced by the intake of fluid
in the diet.
 Low value of Cx will produce sink
condition and favor rapid dissolution.
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2- Physico-chemical factors affecting

drug dissolution
2.1- Particle Size
 The effective surface area (A) of the drug is
increased enormously by a reduction in the
particle size.
 Particle size reduction to a micronized form
increased the absorption of low aqueous
solubility drugs such as griseofulvin,
nitrofurantoin, and many steroids.
 Improved bioavailability has been observed with
griseofulvin, digoxin (the drug absorption is
dissolution rate- limited)
2- Physico-chemical factors affecting

drug dissolution
Follow; 2.1- Particle Size
 Smaller particle size results in an increase in
the total surface area of the particles,
enhances water penetration into the particles,
and increases the dissolution rates.
 With poorly soluble drugs, a disintegrant
may be added to the formulation to ensure
rapid disintegration of the tablet and release
of the particles.
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Follow; 2.1- Particle Size

Limitation of particle size reduction:
1. No effect on bioavailability of drugs whose
absorption was not dissolution rate- limited.
2. In case of poorly soluble, hydrophobic drug,
extensive particle size reduction can increase the
tendency of particles to aggregate in the aqueous GIT
fluids with consequent reduction in the effective
surface area, dissolution rate and bioavailability
3. Certain drug such as penicillin G and erythromycin
are unstable in gastric fluids. Hence, increased rate of
dissolution will result in increased drug degradation.
2.2 Salt form

 Salts of weak acids and weak bases
generally have much higher aqueous
solubility than the free acid or base.
 According to Noyes Whitney equation,
the dissolution rate is influenced by the
solubility (Cs) that the drug exhibits in
the diffusion layer surrounding each
dissolving drug particle.
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Follow; 2.2 Salt form

 For weak electrolytes, the solubilities in the
diffusion layer (Cs) are pH –dependent.
 The pH in the diffusion layer could be
changed by the salt form even though the
bulk pH of the GIT fluids remained at the
same value.
 Therefore if the drug can be given as a salt
the solubility can be increased and
dissolution improved.

A- Dissolution of weak acids in gastric
fluids by a strong base salt like sodium
and potassium salts (ex. Barbiturates,
penicillin V and sulfonamides)
 The potassium salt of penicillin V yields
higher peak plasma concentrations of the
antibiotic than dose the free acid.
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 The pH of the diffusion layer surrounding
each particle of the salt form would be higher
(5-6) than the low bulk pH (1-3) of the gastric
fluids due to neutralizing action of the strong
alkali cations (K+ or Na+) present in the
diffusion layer.
 Since the weak acidic drug has a relatively
high solubility at elevated pH in the diffusion
layer, dissolution of the drug particles will be
faster.

 When dissolved drug diffuses out of the
diffusion layer into the bulk of gastric fluid
with lower pH, precipitation of the free acid
form occurs.
 The precipitated form will be very fine, non-
ionized, wetted drug particles with a very
large effective surface area.
 This condition facilitate re-dissolution of the
precipitated particles.
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schematic representation of the dissolution process of a salt

form of a weak acidic drug in gastric fluid

 Not all water soluble salts have the desirable
therapeutic advantages, e.g., the sulfonylurea oral
hypoglycemic drug: tolbutamide and tolbutamide
sodium.
 Oral administration of the sodium salt results in a very rapid
and dramatic reduction in blood glucose to about 65% to 70
% of control levels. The response resulted in an undesirable
degree of hypoglycemia
 The more slowly dissolving free acid produces a gradual
decrease in blood sugar to about 80% of control levels,
which is observed about 5 hours after administration. The
free acid is more useful form of the drug for treatment of
diabetes.
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 B- An alternative method of increasing the
dissolution rate of a weak acidic drug in
gastric fluid is the inclusion of non-toxic
basic substances in a solid dosage form of
the free acid.
 The inclusion of aluminum dihydroxy
aminoacetate and magnesium carbonate in
aspirin tablets to increase gastric dissolution
and oral bioavailability.

 C- With weakly basic drugs, a strong acid
salt is prepared like the hydrochloride salt of
chlorpromazine
 The presence of strongly acidic anions (Cl-) in the
diffusion layer will increase the solubility of the
drug (Cs)
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2.3- Crystal form

2.3.1- Polymorphism
 Polymorphism refers to the arrangement
of a drug in various crystal forms
(polymorphs)
 Polymorphs have the same chemical
structure but different physical
properties, such as solubility, stability,
melting point, density, hardness, and
compression characteristics.
Follow; 2.3- Crystal form

2.3.1- Polymorphism
 Chloramphenicol palmitate, for example, has
several crystal forms (stable (A), meta-stable (B)
and un-stable ( C ) ) and when given orally as a
suspension, the drug concentration in the body
depend on the percentage of B- polymorph in the
suspension
 Stable polymorph (A) has higher stability and least
aqueous solubility
 The B-form is sufficiently stable and more soluble
and better absorbed than A- form
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2.3.2- Amorphous solid
 A drug may exist in different crystalline forms and
in an amorphous form.
 The amorphous form is usually more soluble and
rapidly dissolving than the corresponding
crystalline forms of a poorly soluble drug.
 The amorphous form of the antibiotic novobiocin is
more soluble, more rapidly dissolving and more
readily absorbed after oral administration of its
aqueous suspension than the crystalline form.
 The crystalline form is therapeutically ineffective

2.3.3- Solvates
 Some drugs interact with solvent during
preparation to form a crystal called solvate.
 Water may form a special crystal with drugs
called hydrates.
 For example, erythromycin forms different
hydrates which may have quite different
solubility compared to the anhydrous form of
the drug
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2.3.3- Solvates
 Generally, the greater the solvation in the
crystal, the lower is the solubility and
dissolution rate in the solvent identical to the
solvation molecules
 Ampicillin trihydrate, for example, was
reported to be less absorbed from hard
gelatin capsule or aqueous suspension than
the anhydrous form of ampicillin due to
faster dissolution of the later
Dissolution testing
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Dissolution Apparatus
(USP Apparatus I and II)
 The apparatus consists of a motor, a metallic drive
shaft, a cylindrical basket, and a covered vessel
made of glass or other inert transparent material.
 The contents are held at 37o C ± 0.5o C.
 The agitation is achieved by the smoothly rotating
stirring element (basket or paddle)
 The vessel is cylindrical with hemispherical bottom
and sides that are flanged at the top. It is 160- 175
mm high and has an inside diameter of 98- 106
mm, and a nominal capacity of 1000 ml.
Dissolution Apparatus
(USP Apparatus I and II)
 A fitted cover may be used to retard evaporation
but should provide sufficient openings to allow
ready insertion of a thermometer and allow
withdrawal of samples for analysis.
 The shaft rotation speed should be maintained
within a range of 25- 150 rpm.
 To the shaft a basket or paddle is fitted into
position.
 The distance between the inside bottom of the
vessel and basket is 25 mm.
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In vitro simulation of in vivo

dissolution
 Some of the basic aspects of the dissolution test
have their origins in general condition in the human
body.
 The test is conducted at 37o C.
 The use of a 900- ml volume was determined in
order to be enough to establish sink conditions (at
least three times saturation) for most active
pharmaceutical ingredients.
 Dissolution media were developed to mimic the pH
of the gastrointestinal tract (water, simulated gastric
fluid, simulated intestinal fluid, buffers,…..)

dissolution
 Hydrodynamics in in vitro experiments (to simulate
gastrointestinal motility) are reflected by the design of
the apparatus, the agitation intensity, the flow
and/or volume, the viscosity of the medium and
practical issues, such as the position of the dosage
form during the experiment.
 The paddle or basket rotation is designed to produce
reproducible hydrodynamics that can be consistent
from lab to lab. The real physical purpose of the
agitation is to remove the drug-saturated layer of
dissolution from around the dosage and replace it with
fresh medium.
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dissolution
 Flask shape has affected the hydrodynamics
of systems and consequently it was
considered better to have flask of uniform
hemispherical shape.
 The distance between the inside bottom of
the vessel and the basket is 25 mm to
simulate in vivo hydrostatic pressure.
Drug dissolution profile
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1.6. Drug stability and hydrolysis

in GIT
 Acid and enzymatic hydrolysis of drugs in GIT is
one of the reasons for poor bioavailability.
Acid hydrolysis
 Both penicillin G and erythromycin are susceptible
to acid hydrolysis.
 The extent of hydrolysis and hence the extent of
absorption is greatly affected by:
1. The residence time in the stomach
2. The dissolution rate.
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Follow;1.6. Drug stability and

hydrolysis in GIT
 Penicillin G (half life of degradation = 1 min

at pH = 1)
 Rapid dissolution leads to poor
bioavailability (due to release large portion
of the drug in the stomach, pH = 1.2)
Follow1.6. Drug stability and

hydrolysis in GIT
 Techniques to minimize the extent of acid hydrolysis
(improve the bioavailability) of unstable drug.
1. Enteric coating
 This technique delay the dissolution of drug until
reaching the small intestine.
 The enteric coat resist dissolution in acidic pH (gastric
fluid) and dissolve readily in intestinal fluid pH
 Ex. Erythromycin enteric coated tablets
 The enteric coated tablets showed variable drug
bioavailability.
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hydrolysis in GIT
2- Pro- Drugs
 It is a chemical derivative of the parent drug which
exhibit limited solubility in gastric fluids but
liberate the parent drug in the small intestine.
 Liberation of parent compound from pro-drug is the
rate limiting step in bioavailability, either positively
or negatively.
 Ex. 1- erythromycin stearate (liberate the free base
in the small intestine).

hydrolysis in GIT
Follow; 2- Pro- Drugs
 Ex. 2- erythromycin estolate (Lauryl sulphate salt of
erythromycin propionate)
 The poorly soluble lauryl sulfate salt remains un-dissolved
in the stomach.
 It dissolves and dissociate to give ester erythromycin
propionate in the intestine.
 The ester is better absorbed than the free erythromycin due
to its increased lipid solubility.
 In blood, the ester hydrolysis to release erythromycin.
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1.7. Complexation
 Complexation of a drug in the GIT fluids may alter rate
and extent of drug absorption.
 Complexation affects the effective drug concentration of
GIT fluids
1.7.1- Complexation between a drug and normal
components of the GIT:
 Mucin (Intestinal mucosa) + streptomycin = poorly
absorbed complex
 Mucin is a various muco-polysaccharide lining the
mucosal surface of the GIT
 This leads to reduced effective drug concentration at the
site of absorption and reduced drug bioavailability.
Follow; 1.7. Complexation

1.7.2- Complexation between a drug and
dietary components:
 Calcium (dairy products, milk, antacids,
…..etc) + Tetracycline = poorly soluble and
absorbed complex (food-drug interaction)
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excipients present in the dosage forms:
(A) leading to reduced bioavailability
 Tetracycline + dicalcium phosphate (diluent in
tablets and capsules) = poorly soluble and absorbed
complex
 Amphetamine + Carboxyl methylcellulose (tablet
additive) = poorly absorbed complex
 Phenobarbitone + PEG 4000 = poorly absorbed
complex

(B) leading to beneficial effect
 Polar drugs + complexing agent = well-
absorbed lipid soluble complex
(dialkylamides + prednisone)
 Lipid soluble drug + water soluble
complexing agent = well-absorbed water
soluble complex (cyclodextrine)
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(C) leading to no effect
 Drug + excipients = soluble complexes
rapidly dissociate to liberate the free drug
 The effect on drug absorption is determined
by the rate of complex dissociation
1.8- Adsorption
 Certain insoluble substance may adsorb co-
administered drugs leading to poor absorption
 Charcoal (antidote in drug intoxication)
 Cholestyramine (insoluble anionic exchange
resins)
 Adsorption decreases the effective drug
concentration in solution at the site of absorption.
 The readily reversible drug- adsorbent interaction
will have no effect or affect only the rate not the
extent of drug absorption.
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Follow; 1.8- Adsorption

 Ex.1. Promazine + attapulgite = readily
reversible complex (affect only the rate of
absorption)
 Ex.2. Promazine + charcoal = not readily
reversible complex (affect the rate and extent
of drug absorption)
 Cyanocobolamin + Talc ( a glidant in tablet)
= affect both the rate and extent of drug
absorption

oral drug absorption
2.1- pH of the GIT fluids
 The pH of GI fluids varies
considerably along the length
of the gastrointestinal tract.
 Gastric fluid is highly acidic
(1 – 3.5) in healthy people in
the fasted state.
 The duodenum ( 6 to 6.5)
 Jejunum and ileum (7- 8)
 Large intestine (7- 8)
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2- Physiological factors affecting oral drug absorption

Follow; 2.1- pH of the GIT fluids
Factors affecting the normal pH ranges of GIT fluids
 1- Food ingestion
◦ Following the ingestion of a meal, the gastric juice is
buffered to a less acidic pH, which is dependent on meal
composition
◦ Typical gastric pH values following a meal are in the range
3- 7.
◦ Depending on meal size, the gastric pH returns to the lower
fasted-state values within 2 -3 hours.
◦ Thus, only a dosage form ingested with or soon after a meal
will encounter theses higher pH values, which may affect the
chemical stability of a drug, drug dissolution or absorption.

 2- Diurnal cycle of gastric acidity
 A circadian rhythm of basal gastric acidity is
known to occur with acid output being highest in
the evening and lowest in the morning.
 3- General health of the individual
 4- The presence of localized disease
(gastric and duodenal ulcers)
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 5- Drug therapy
◦ Ex. Anti-cholinergic drugs inhibits gastric secretion
◦ Ex. Antacid increase pH
 6- Gender
◦ There is a sex-related difference in human gastric acid
secretion
◦ (pH of 2.16 for men and 2.79 in women)
 7- Age
◦ It has always been assumed that gastric acid secretion
decreased with age.

 The effect of pH on drug absorption:
◦ 1- The GI pH may influence the chemical
stability of the drug in the lumen
◦ Chemical degradation due to pH-dependent
hydrolysis can occur in the GI tract.
◦ The result of this instability is incomplete
bioavailability, as only a fraction of the
administered dose reaches the systemic
circulation in the form of intact drug.
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 Follow; The effect of pH on drug absorption:
◦ 2- Affects the degree of ionization of weak
electrolytes.
◦ 3- Affects the dissolution rate and /or absorption,
if the drug is a weak electrolyte.

2.2- Surface area of GIT absorption site
 The small intestine has the largest effective surface
area due to presence of villi and microvilli
 The stomach and large intestine have relatively
small absorptive surface areas due to absence of
villi and microvilli.
 Certain drugs are absorbed from the stomach but
with lower extent compared with the small intestine
 Large intestine plays a significant role in absorption
of slowly absorbed drug and drugs need to be
degraded by bacterial flora before absorption (ex.
Sulphasalazine.)
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2.3- Gastric emptying rate
 The process of gastric emptying is

extremely complex and is influenced by
many factors.
 Most drugs are not absorbed from the
stomach and are therefore dependent on
the gastric emptying process to deliver
them to their site of absorption.

Follow; 2.3- Gastric emptying rate
 Factors enhancing gastric emptying rate:
◦ Intake of fluids
◦ Hunger
◦ Anxiety
◦ The patient’s body position (lying on the
right side)
◦ Intake of antiemetics (ex. Metoclopramide)
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 Factors retarding gastric emptying rate:
 Meals that contain large fragments of food or are nutrient-
dense will take longer to empty and hence will delay the
passage of dosage forms to the small intestine (fatty foods,
highly viscous meal).
◦ Hence, unless the drug is irritating to gastric mucosa, it should not be
administered with bulky meal
 Mental depression
 Gastric ulcers
 Pyloric stenosis
 Hypothyroidism
 Patient body position (lying on the left side)
 Anticholinergic drugs

 Gastric emptying follows a circadian rhythm
with slower emptying occurring in the afternoon
compared with the morning.
 These numerous factors contribute to high inter-
subject and intra-subject variations in oral drug
bioavailability
 The gastric emptying rate of solution type dosage
forms and suspensions of fine particles is generally
much faster and less variable than solid, non-
disintegrating unit dosage forms.
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 Delay in gastric emptying rate may lead
to:
 1- Delay the rate of drug absorption
(reduction in the rate not the extent of
absorption):
◦ Decrease the intensity of the therapeutic
response.
◦ Increase the onset of action
◦ Ex. Aspirin, barbiturate and cephalosporin

 Delay in gastric emptying rate may lead
to:
 2- Decreasing the effective drug
concentration at the site of absorption
◦ By decreasing the stability of drugs susceptible to
chemical (acidic pH) or enzymatic degradation in
the stomach
◦ Leading to reduction in the rate and extent of
drug absorption.
◦ Ex. Penicillin
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 Delay in gastric emptying rate may
lead to:
 3- Delay the onset of therapeutic activity
without affecting the intensity
◦ Ex. Enteric coated tablets
 4- Increase the drug dissolution (enhance
bioavailability)
◦ Ex. Poorly soluble weak basic drugs
(nitrofurantoin)
◦ Exhibited enhanced bioavailability in presences
of food

2.4- Food
A- Reducing gastric emptying rate
 Food (especially fatty, solid and hot food)
slows the gastric emptying rate under normal
physiological conditions.
 Consequently, the gastric residence time of
the concurrently administered drugs is
prolonged.
 This may lead to:
◦ 1- Reduced rate of absorption of the
concurrently administered drug
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Follow; 2.4- Food
Follow; A- Reducing gastric emptying rate
 2- A delay in the onset of therapeutic
action. This is of clinical concern when
a rapid onset of action is required, as for
analgesics, sedatives, and hypnotics.
For this group of drugs, administration
under fasting condition may be
preferable.

Follow; 2.4- Food
Follow; A- Reducing gastric emptying rate
 3- Reduced extent of absorption for those
acid-labile drugs such as penicillin,
erythromycin, and cephalosporin, (hydrolysis is
increased as a result of increased gastric
residence time).
 4- Increased extent of absorption for poorly
aqueous soluble drugs (Increased dissolution
due to prolonged gastric residence time and
increased gastric secretion in response to food
administration)
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Follow; 2.4- Food
B- Stimulation of gastrointestinal secretion
 Increased acidic and enzymatic secretions in
response to ingestion of food may lead to:
◦ Reduced drug bioavailability; For drugs
susceptible to chemical or enzymatic degradation.
◦ Enhanced absorption of poorly soluble drugs
(griseofulvin) due to secretion of bile salts
(S.A.A.) in response to ingestion of fatty meal.

Follow; 2.4- Food
C- Competition between food components
and drugs specialized absorption
mechanisms
 Between nutrients and drugs of similar
chemical structures leading to competitive
inhibition of drug absorption
◦ Ex. L-Dopa + amino-acids (resulted from
breakdown of ingested proteins) = competitive
inhibition of L-Dopa absorption
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Follow; 2.4- Food
D- Complexation of drugs with
components in the diet
 Tetracycline will form poorly soluble
complexes with metal ions such as Ca++, Mg++,
Fe++, and Al+++ .
 Therefore, concurrent administration of
tetracycline and foods or drugs that contain
these metal ions should be avoided.
 Reduced oral bioavailability may lead to sub-
therapeutic drug level and treatment failure.

Follow; 2.4- Food
E- Increased viscosity of the GIT fluids
 This result in reduction of drug dissolution
rate by decreasing D and by reducing drug
diffusion from the lumen to the absorbing
membrane lining the GIT.
 These effects tend to decrease drug
bioavailability if the drug bioavailability is
dissolution limited.
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Follow; 2.4- Food
F- Food induced changes in blood flow
 Blood flow to the GIT and liver increases shortly after a meal.
This will increase the rate of drug presentation to the liver.
 Consequently, a larger fraction of drug escape first pass
metabolism.
 This is because the enzyme systems responsible for drug
metabolism become swamped (saturated by the increased rate of
drug presentation to the site of biotransformation).
 So, food increases the amount of intact drug reaching the
systemic circulation.
 An increase in oral bioavailability has been observed for several
drugs including hydralazine and some beta-adrenergic blocking
agents such as labetolol, metoprolol and propranolol.

2.5- Malabsorption
 Malabsorption is any disorder with impaired
absorption of fat, carbohydrate, proteins and
vitamins.
 Drug induced malabsorption has been
observed after administration of neomycin,
phenytoin and anticancer agents.
 Results in impaired absorption of vitamins
(B12, D, K) folic acid, iron, calcium….
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3- Dosage form factors affecting oral drug

absorption
3.1- Role of dosage forms
 The bioavailability of a drug decrease in the
following order: solution > suspension > capsule >
tablet > coated tablet.
 The type of oral dosage forms affects the possible
number of intervening steps between administration
and appearance of dissolved drug in the GIT fluids.
 The greater the number, the lower the
bioavailability of a given drug.
Follow; 3- Dosage form factors affecting

3.1- Role of Excipients
Diluents
 Australian outbreak of phenytoin intoxication.
 Many epileptic patients who had been stabilized with
sodium phenytoin capsules containing calcium sulphate
dihydrate as the diluent, developed clinical features of
phenytoin over dosage when given sodium phenytoin
capsules containing lactose as the diluent
 This is because the excipient calcium sulphate
dihydrate forms a poorly absorbed calcium-phenytoin
complex
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Follow; 3.1- Role of Excipients
Lubricants and Glidants
 Talc (in tablets as a glidant) +
Cyanocobolamin = Adsorbed drug =
decreased drug absorption
 Excessive quantities of magnesium
stearate in drug formulation = retard drug
dissolution = slow rate of drug absorption

Follow; 3.1- Role of Excipients
Surfactants
(Emulsifying, solubilizing, suspension stabilizer
and wetting agents)
 Generally increase the dissolution rate and drug
absorption rate.
 Ex. Phenacetin + Tween 80 (to prevent aggregation
in aqueous suspension) = prevent aggregation =
increase effective surface area = increase
dissolution rate = increase drug absorption
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Bio-pharmaceutics Classification
System (BCS)
 The (BCS) has been developed to provide a
scientific approach to allow for the
prediction of in vivo pharmacokinetics of
oral immediate release (IR) drug products by
classifying drug compounds based on their
solubility related to dose and intestinal
permeability in combination with the
dissolution properties of the dosage form.
Follow; Introduction
 The importance of drug dissolution in the
gastrointestinal tract and permeability across
the gut wall barrier in the oral absorption
process has been well known since the
1960s, but the research carried out to
constitute the BCS has provided new
quantitative data of great importance for
modern drug development especially within
the area of drug permeability.
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According to BCS, drug substances

are classified as follows:
 Class I - High Permeability, High
Solubility
 Class II - High Permeability, Low
Solubility
 Class III - Low Permeability, High
Solubility
 Class IV - Low Permeability, Low
Solubility
Class Boundaries
 A drug substance is considered HIGHLY
SOLUBLE when the highest dose strength is
soluble in < 250 ml water over a pH range of
1 to 7.5
 A drug substance is considered HIGHLY
PERMEABLE when the extent of absorption
in human is determined to be > 90% of an
administered dose.
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Class Boundaries
 A drug product is considered to be
RAPIDLY DISSOLVING when > 85% of
the labeled amount of drug substance
dissolves within 30 minutes using USP
apparatus I or II in a volume of < 900 ml
buffer solutions.
Class I Drugs
 The rate limiting step is drug dissolution
 If dissolution is very rapid, then gastric
emptying rate becomes the rate determining
step.
 E.g. Metoprolol, Diltiazem, Verapamil,
Propranolol.
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Class II Drugs
 In vivo drug dissolution is the rate limiting step
for absorption
 The absorption for class II drugs is usually
slower than class I and occurs over a longer
period of time.
 In vitro- in vivo correlation (IVIVC) is usually
expected for class I and class II drugs.
 E.g. Phenytoin, Danazol, Ketoconazole,
Mefenamic acid, Nifedipine.
Class III Drugs

 For class III drugs, permeability is rate limiting step
for drug absorption.
 These drugs exhibit a high variation in the rate and
extent of drug absorption.
 Since the dissolution is rapid, the variation is
attributable to alteration of physiology and
membrane permeability rather than the dosage form
factors.
 E.g. Cimetidine, Acyclovir, Neomycin B, Captopril.
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Class IV Drugs
 Class IV drugs exhibit a lot of problems for
effective oral administration.
 Fortunately, extreme examples of class IV
compounds are the exception rather than the
rule and are rarely developed and reach
market.
 Nevertheless a number of class IV drugs do
exist. E.g. Taxol.
Applications of BCS in oral drug

delivery technology
 Once the solubility and permeability
characteristics of the drug are known it
becomes an easy task for the research
scientist to decide upon which drug
delivery technology to follow or
develop.
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Class I Drugs
 The major challenge in development of drug
delivery system for class I drugs is to
achieve a target release profile associated
with a particular pharmacokinetic and/or
pharmacodynamic profile.
 Formulation approaches include both control
of release rate and certain physicochemical
properties of drugs like pH-solubility profile
of drug.
Class II Drugs
 The system that are developed for class
II drugs are based on micronisation,
lyophilization, addition of surfactants,
formulation as emulsions and micro
emulsions systems, use of complexing
agents like cyclodextrins.
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Class III Drugs

 ClassIII drugs require the technologies
that address to fundamental limitations
of absolute or regional permeability.
Peptides and proteins constitute the part
of class III and the technologies
handling such materials are on rise now
days.
Class IV Drugs
 Class IV drugs present a major
challenge for development of drug
delivery system and the route of choice
for administering such drugs is
parenteral with the formulation
containing solubility enhancers.
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Biopharmaceutics (LADME)
Introduction
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Introduction:
Routes of administration
Introduction
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Introduction
Drug distribution
 After a drug is absorbed into plasma, the drug
molecules are distributed throughout the body by the
systemic circulation.
 The drug molecules are carried by the blood to the
target site (receptor) for drug action and to other
(non-receptor) tissues as well, where side effects or
adverse reactions may occur.
 Drug molecules are distributed to eliminating organs,
such as the liver and kidney, and to non-eliminating
tissues, such as the brain, skin, and muscle.
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Drug distribution
 In pregnancy, drugs may cross the placenta
and may affect the developing fetus.
 Drugs can also be secreted in milk via the
mammary glands.
 A substantial portion of the drug may be
bound to proteins in the plasma and/or
tissues.
 Lipophilic drugs deposit in fat, from which the
drug may be slowly released
Drug distribution:
Body fluids
 Mixing of a drug solution in the blood occurs rapidly
due to high flow rate and rapid turn-over.
 Drug molecules rapidly diffuse through a network of
fine capillaries to the tissue spaces filled with
interstitial fluid.
 The interstitial fluid plus the plasma water is termed
extracellular water, because these fluids reside
outside the cells.
 Drug molecules may further diffuse from the
interstitial fluid across the cell membrane into the cell
cytoplasm
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Drug distribution:
Body fluids
Relative distribution of water in the body
plasma
water, 3
intercellular
water, 12
intracellular
water, 27
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Drug distribution:
Diffusion through cell membrane
 Drug distribution is generally rapid, and most
small drug molecules permeate capillary
membranes easily.
 The passage of drug molecules across a cell
membrane depends on the physicochemical
nature of both the drug and the cell
membrane.
 The molecular size plays an important role in
drug diffusion across the membrane.
Drug distribution:
 Cell membranes comprise
protein and a bilayer of
phospholipid, which acts as a
lipid barrier to drug uptake.
 Thus, lipid-soluble drugs
generally diffuse across cell
membranes more easily than
highly polar or water-soluble
drugs.
 Accordingly, non-ionized form
of the drug can permeate.  .
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Drug distribution:
 Small drug molecules generally
diffuse more rapidly across cell
membranes than large drug
molecules.
 If the drug is bound to a
plasma protein such as albumin,
the drug–protein complex
becomes too large for easy
diffusion across the cell or even  .
capillary membranes
Drug distribution
 Diffusion and Hydrostatic Pressure
 The processes by which drugs transverse capillary
membranes include passive diffusion and hydrostatic
pressure.
 Passive diffusion is the main process by which most drugs
cross cell membranes.
 The driving force for passive diffusion is the concentration
gradient.
 Passive diffusion is described by Fick's law of diffusion
 So the contributing factors include the partition coefficient,
diffusion coefficient and the plasma concentration.
 Additional factors include membrane permeability and tissue
affinity to drug.
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Drug distribution
 Diffusion and Hydrostatic Pressure
 Hydrostatic pressure represents the pressure gradient
between the arterial end of the capillaries entering the tissue
and the venous capillaries leaving the tissue.
 The pressure of arterial end of the capillaries is 8 mmHg
higher than the tissue. This will lead to filtration of the fluid
into the tissue.
 The filtered fluid returns to the venous capillaries leaving the
tissue (venous capillaries has lower pressure).
 Hydrostatic pressure is responsible for penetration of water-
soluble drugs into spaces between endothelial cells and
possibly into lymph.
Drug distribution
 Distribution Half-Life, Blood Flow, and Drug
Uptake by Organs
 Because the process of drug transfer from the capillary into
the tissue fluid is mainly diffusional, the membrane
thickness, diffusion coefficient of the drug, and
concentration gradient across the capillary membrane are
important factors in determining the rate of drug diffusion.
 Kinetically, if a drug diffuses rapidly across the membrane in
such a way that blood flow is the rate-limiting step in the
distribution of drug, then the process is perfusion or flow
limited.
 In congestive heart failure, decreased cardiac output, results
in impaired blood flow, which may reduce renal clearance
through reduced filtration pressure and blood flow.
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Drug distribution
 Distribution Half-Life, Blood Flow, and Drug Uptake
by Organs
 If drug distribution is limited by the slow diffusion of drug across
the membrane in the tissue, then the process is termed diffusion or
permeability limited.
 Drugs that are permeability limited may have an increased
distribution volume in disease conditions that cause inflammation
and increased capillary membrane permeability.
 The delicate osmotic pressure balance may be altered due to
albumin and/or blood loss or due to changes in electrolyte levels in
renal and hepatic disease, resulting in net flow of plasma water
into the interstitial space (edema).
 This change in fluid distribution may partially explain the increased
extravascular drug distribution during some disease states
Drug distribution
 Distribution Half-Life, Blood Flow, and Drug
Uptake by Organs
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Drug distribution
 Distribution Half-Life, Blood Flow, and Drug Uptake by Organs
 If each tissue has the same ability to store the drug, then the
distribution half-life is governed by the blood flow.
 Vascular tissues such as the kidneys and adrenal glands achieve
95% distribution in less than 2 minutes.
 In contrast, drug distribution time in fat tissues and other less
vascular organs takes 4 hours
 Under normal conditions, limited blood flow reaches the muscles.
 During exercise, the increase in blood flow may change the fraction
of drug reaching the muscle tissues. Diabetic patients receiving
intramuscular injection of insulin may experience the effects of
changing onset of drug action during exercise.
 During injury or when blood is lost, constriction of the large veins
redirect more blood to needed areas and, therefore, affect drug
distribution.
Drug distribution
 Distribution Half-Life, Blood Flow, and Drug Uptake by Organs
 Some tissues have great ability to store and accumulate
drug.
 For example, the antiandrogen drug flutamide and its active
metabolite are highly concentrated in the prostate. The
prostate drug concentration is 20 times that of the plasma
drug concentration; thus, the antiandrogen effect of the
drug is not fully achieved until distribution to this receptor
site is complete.
 Digoxin is highly bound to myocardial membranes.
 Iodine is concentrated in the thyroid gland and tetracycline

in developing teeth and bone.
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Drug distribution
 Drug accumulation
 This is not only dependent on tissue perfusion but
also dependent on the affinity of drug to the
tissue.
 Drugs with a high lipid solubility tend to
accumulate in adipose tissue. This process is
reversible. Because the adipose tissue is poorly
perfused with blood, drug accumulation is slow.
However, once the drug is concentrated in fat,
drug removal may also be slow. For example DDT
(dichlorodiphenyltrichloroethane) is highly lipid
soluble and remains in fat tissue for years.
Drug distribution
 Permeability of capillaries and cell
membrane (diffusional barrier)
 The brain is well perfused with blood, but many
drugs with good aqueous solubility have high
kidney, liver, and lung concentrations and yet little
or negligible brain drug concentration.
 This is due to the high diffusional resistance from
the blood brain barrier (BBB)
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Drug distribution:
diffusional barrier to the brain
 In cerebral capillaries, Blood-brain barrier
endothelial cells have
overlapping ‘tight’ junctions
restricting passive diffusion.
 The surrounding capillary
basement membrane is
closely applied to the
peripheral processes of
astrocytes, which play an
important part in neuronal
nutrition.
Drug distribution:
 To pass from capillary blood
to the brain, most drugs  Blood-brain barrier
have to cross the
endothelium, the basement
membrane and the
peripheral processes of
astrocytes by simple
diffusion or filtration.
 Some drugs cannot readily
cross these restrictive
barriers, which are
collectively referred to as the
blood–brain barrier.
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Drug distribution:
 Enzymatic barrier  Blood-brain barrier
 In addition to this structural barrier,
there is also a metabolic or enzymatic
blood–brain barrier, which is mainly
associated with the peripheral
processes of astrocytes.
 Many neurotoxic agents (e.g. free fatty
acids, ammonia) can readily cross the
capillary endothelium, but are
metabolized before they reach the
CNS.
 In addition, capillary endothelial cells
express a transport protein (P-
glycoprotein), which actively extrudes
many drugs, including most opioids,
from the CNS.
Drug distribution
 Permeability of BBB to drugs
 Certain metabolic substrates and hormones, such as
glucose, insulin, l-amino acids, l-thyroxine and transferrin,
normally cross the BBB by endocytosis or carrier transport.
 In addition, many low molecular weight, lipid-soluble drugs
(e.g. general anaesthetics, local anaesthetics, opioid
analgesics) can cross the barrier and enter the CNS,
although their access may be restricted by P-glycoprotein.
 In contrast, when drugs are highly protein bound (e.g.
tolbutamide, warfarin), only the unbound fraction can readily
diffuse from blood to the CNS, so that the concentration of
these drugs in the brain may be 1–2% of the total plasma
level.
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Drug distribution
 Drug permeability of BBB
 Approximately 25% of thiopental is initially taken up by the
brain due to its high lipid solubility and the extensive blood
supply of the CNS. As the plasma concentration falls,
thiopental is progressively taken up by less well-perfused
tissues which have a higher affinity for the drug. In
consequence, intravenous thiopental is rapidly redistributed
from brain to muscle and finally to subcutaneous fat.
 Redistribution is mainly responsible for its short duration of
action, and its final elimination from the body may be
delayed for24 hours.
 The normal impermeability of the BBB can be modified by
diseases as inflammation, oedema and acute and chronic
hypertension.
Drug distribution:
Apparent volume of distribution
 The concentration of drug in the plasma or tissues depends on
the amount of drug systemically absorbed and the volume in
which the drug is distributed.
 The apparent volume of distribution (VD) is used to estimate
the extent of drug distribution in the body.
 Although the VD does not represent a true anatomical, or
physical volume, it represents the result of dynamic drug
distribution between the plasma and the tissues and accounts
for the mass balance of the drug in the body.
 .
 .
 .
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Protein binding of drugs

 Many drugs interact with plasma or tissue proteins or with other
macromolecules, such as melanin and DNA, to form a drug–
macromolecule complex.
 The formation of a drug protein complex is often named drug–protein
binding.
 Drug–protein binding may be a reversible or an irreversible process.
 Irreversible protein binding results from covalent chemical bonding.
 Irreversible drug binding accounts for certain types of drug toxicity that
may occur over a long time period, as in the case of chemical
carcinogenesis, or within a relatively short time period, as in the case
of drugs that form reactive chemical intermediates.
 For example, the hepatotoxicity of high doses of acetaminophen is due
to the formation of reactive metabolite intermediates that interact with
liver proteins.

 Most drugs bind or complex with proteins by
a reversible process.
 Reversible drug–protein binding implies that
the drug binds the protein with weaker
chemical bonds, such as hydrogen bonds or
van der Waals forces.
 Reversible drug–protein binding is of major
interest in pharmacokinetics.
 .
 .
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 Only the free drug can diffuse to the tissue and as its
concentration in plasma falls, protein-bound drug
rapidly dissociates. Consequently, a continuous
concentration gradient is present for the diffusion of
drugs from plasma to tissues.
 Albumin binds drugs as salicylates, indomethacin,
tolbutamide and oral anticoagulants.
 Globulins bind many basic drugs (e.g. bupivacaine,
opioid analgesics). Plasma globulins also play an
important role in the binding of minerals, vitamins
and hormones.
Protein binding of drugs:

drug displacement and competition
 Drugs and endogenous substrates that are extensively bound to
proteins may compete for (and be displaced from) their binding
sites.
 Displacement of drugs from plasma proteins can affect the
pharmacokinetics of a drug in several ways:
 (1) Increase the free drug concentration
 (2) Increase the free drug concentration that reaches the receptor
sites directly, causing a more intense pharmacodynamic (or toxic)
response.
 (3) Transient increase in VD and decreasing partly some of the
increase in free plasma drug concentration
 (4) increase the free drug concentration, resulting in more drug
diffusion into tissues of eliminating organs, particularly the liver and
kidney, resulting in a transient increase in drug elimination.
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Protein binding of drugs:

drug displacement and competition
 However, it is now believed that,
binding of drugs at clinical
concentrations only occupies a small
proportion of the available binding sites
and does not approach saturation.
Consequently, competition between
drugs resulting in clinically significant
displacement from plasma protein
binding is rare.
Plasma protein binding and drug

distribution and elimination
 In general, drugs that are highly bound to
plasma protein have reduced overall drug
clearance.
 For a drug that is metabolized mainly by the
liver, protein binding prevents the drug from
entering the hepatocytes, resulting in reduced
drug metabolism by the liver.
 In addition, molecularly bound drugs may not
be available as substrates for liver enzymes,
thereby further reducing the rate of
metabolism.
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Plasma protein binding and drug

distribution and elimination
 Protein-bound drugs act as larger molecules that cannot diffuse
easily through the capillary membranes in the glomeruli.
 The elimination half-lives of some drugs, such as the
cephalosporins, which are excreted mainly by renal excretion,
are generally increased when the percent of drug bound to
plasma proteins increases.
 Other examples include:
 Doxycycline, which is 93% bound to serum proteins, has an
elimination half-life of 15.1 hours, whereas oxytetracycline, which
is 35.4% bound to serum proteins, has an elimination half-life of
9.2 hours.
 In contrast drug that is both extensively bound and actively
secreted by the kidneys, such as penicillin, has a short elimination
half-life, because active secretion takes preference in removing or
stripping the drug from the proteins as the blood flows through the
kidney.
Protein Binding and pathological state

 Binding to plasma proteins is modified in pathological conditions
associated with hypoalbuminaemia, as in liver cirrhosis, nephrosis,
trauma or burns. In these conditions, the concentration of the unbound
drug tends to increase and may result in toxic effects (e.g. with
phenytoin or prednisolone).
 Significant changes are more likely when high doses of drugs are used,
or when drugs are given intravenously. In these conditions, plasma
proteins may be saturated, causing a disproportionate increase in the
concentration of the unbound drug.
 Tissues and organs that are well perfused (e.g. brain, heart, abdominal
viscera) may receive a higher proportion of the dose, increasing the
potential of toxic effects.
 Similar effects may occur in elderly patients and in subjects with renal
impairment, possibly due to alterations in the affinity of drugs for
albumin.
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Drug metabolism:
Presystemic disposition
Drug metabolism:
 First pass effect
 After oral administration drugs permeate through
the enterocytes then pass through the mesentric
vein to the portal vein which will take the drug to
the liver where it will be subjected to extensive
metabolism. This metabolism may take place in
the intestinal mucosal cells.
 This effect is termed the first pass effect and is
responsible for rapid metabolism of the drug
leading to poor oral bioavailability.
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Drug metabolism:
 First pass effect
 This effect may be altered by food or drink.
 E.g. food intake will increase the blood
flow to the liver. This will result in more
drug molecules reaching the liver at the
same time. This will give a chance for more
drug to escape from the hepatic first pass
metabolism.
First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by

Felodipine and Its Interaction with Grapefruit Juice
Wilkinson G. N Engl J Med 2005;352:2211-2221
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First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by

Felodipine and Its Interaction with Grapefruit Juice
● The previous figure shows the first-pass metabolism after oral

administration of a Drug, as Exemplified by Felodipine and Its
Interaction with Grapefruit Juice.
● CYP3A enzymes (e.g., CYP3A4) present in enterocytes of the intestinal
epithelium extensively metabolize felodipine during its absorption, and
on average only 30 percent of the administered dose enters the portal
vein (solid line). Subsequently, CYP3A enzymes in the liver further
metabolize the drug so that only 15 percent of the dose is bioavailable
and finally reaches the systemic circulation and is able to exert its
effects. Grapefruit juice selectively inhibits CYP3A in the enterocyte,
with the net result being an increase in the oral bioavailability of
felodipine by a factor of three, denoted by the asterisks and the
dashed lines.
Effect of Grapefruit Juice on Felodipine Plasma

Concentration (from Bailey et al., Br. J. Clin Pharmacol,
1998, 46: 101-110)
5mg tablet
with juice
without
Cl
Cl
Cl
H Cl
CH3 O 2 C CO 2 CH3 3A4
CH3 O 2 C CO 2 CH3
CH3 N CH3
CH3 N CH3
H
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Grapefruit Juice Facts
 GJ elevates plasma peak drug concentration but not the

elimination t1/2
 GJ reduced metabolite/parent drug AUC ratio
 GJ caused 62% reduction in small intestinal enterocyte 3A4
and 3A5 protein. It does not affect the liver to the same extent
(i.v. pharmacokinetics unchanged)
 GJ effects last ~4 h. This requires new enzyme synthesis
 The effect may be up to 5x Cmax and is highly variable among
individuals depending upon the level of 3A4 in the small
intestine.
Systemic metabolism
(biotransformation)
 Drug molecules are processed by enzymes evolved to cope
with natural compounds
 The drug actions may be increased, decreased or
unchanged.
 Individual variation in the metabolism is genetically
determined.
 There may be several routes of metabolism.
 May not lead to termination of drug action.
 May take place anywhere BUT the liver is main site.
 Not constant - can be changed by other drugs providing the
base of many drug-drug interactions.
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Biotransformation of drugs
 Process by which the drug is chemically converted
in the body to a metabolite with the goal of de-
toxification.
 Biotransformation is usually enzymatic but some
drugs may be changed in non-enzymatic process.
 Drugs may converted to less toxic/effective
materials, more toxic/effective materials
materials with different type of effect or
toxicity
Sites of biotransformation
 Where ever the appropriate enzymes
occur (plasma, kidney, lung, gut wall
and LIVER).
 The liver is ideally placed to intercept
natural ingested toxins and has a
major role in biotransformation
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The liver
Hepatocytes
portal smooth bile
venous endoplasmic
blood reticulum
microsomes
contain cytochrome
systemic P450
arterial dependent
blood mixed function oxidases
venous blood
Types of biotransformation reactions
 Any structural change in a drug molecule may change its

activity
 Phase I - changes drugs and creates site for phase II.
oxidation (adds O) eg. Microsomes (P450); reduction;
hydrolysis (eg. by plasma esterases) and others
 Phase II - couples group to existing (or phase I formed)
conjugation site. E.g. glucuronide (with glucuronic acid),
sulphate and others
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Cytochrome P450 dependent

mixed function oxidases
DRUG METABOLITE
=DRUG+O
O2
microsome
NADPH NADP+
H+ WATER
There are several different types of mixed

function oxidase - different specificity
Cytochrome P450 dependent mixed

function oxidases
CYP
FOUR families 1-4
SIX sub-families A-F
up to TWENTY isoenzymes 1-20
CYP3A4 : CYP2D6 : CYP2C9 : CYP2C19 :CYP2A6
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Biotransformation reactions
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Phase II reactions
(not all in the liver)
 Conjugation of -OH, -SH, -COOH or -CONH with
glucuronic acid to give glucuronides
 Conjugation of -OH with sulphate to give sulphates
 Conjugation of -NH2, -CONH2, aminoacids, sulpha
drugs with acetyl- to give acetylated derivatives
 Conjugation of -halo, -nitrate, epoxide, sulphate with
glutathione to give glutathione conjugates
 All tend to be less lipid soluble and thus easily
excreted and less reabsorbed.
Other (non-microsomal)
reactions
 Hydrolysis in plasma by esterases (suxamethonium by
cholinesterase)
 Alcohol and aldehyde dehydrogenase in cytosolic
fraction of liver (ethanol)
 Monoamine oxidase in mitochondria (noradrenaline,
dopamine, amines)
 Xanthene oxidase (6-mercaptopurine, uric acid
production)
 enzymes for particular drugs (dopa-decarboxylase
etc)
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Factors affecting biotransformation

 Genetic polymorphism
 This depends on the race.
 N-acetylation of isoniazid is genetically determined
with at least two groups being identified including
rapid and slow acetylators.
 Individuals with slow acetylation are subject to
isoniazid-induced toxicity.
 Procainamide and hydralazine are other drugs
undergoing acetylation and demonstrating genetic
polymorphism.
Factors affecting biotransformation
 age (reduced in aged patients & children)

 sex (women slower ethanol metabilizers)
 species (animal model are usually used in early stages of drug
development. However different animal species may have
different metabolic pathways. E.g. Amphetamine is mainly
hydroxylated in rats but deaminated in human and dogs.
 clinical or physiological condition (liver disease may affect the
extent of drug metabolism)
 other drug administration (induction or inhibition)
 food (charcoal grill ++CYP1A) (grapefruit juice --CYP3A)
 first-pass (pre-systemic) metabolism
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Some basic definitions

 Substrate:
Drug is metabolised by the enzyme system
 Inducer:
Drug that will increase the synthesis of CYP450 enzymes. They
will shorten action of drugs or increase effects of those
biotransformed to active agents
 Inhibitor
Drug that will decrease the metabolism of a substrate. They
prolongs action of drugs or inhibits action of those
biotransformed to active agents (pro-drugs).
 BLOCKERS
Acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)
Enzyme Induction
 Leads to production of more enzyme,
usually after 3-4 days of exposure to
inducer
 Most CYPs are inducible except
CYP2D6
 Time course of interaction depends on
half-life of inducer.
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Enzyme Induction
 Rifampicin has short half-life and induction
apparent within 24 hours after administration.
 Phenobarbitone has longer half life so time to
complete induction takes longer.
 Other inducer include carbamazepine,
griseofulvin, chronic use of alcohol and
polycyclic hydrocarbons (Tobacco smoke and
grilled meat).
Enzyme Inhibition
 Enzyme inhibition can take place by many
mechanisms
 Competitive inhibition: in this case the inhibitor and drug-
substrate compete for the same active center on the
enzyme. The substrate and inhibitor may be structurally
related. Increasing the drug-substrate concentration may
displace the inhibitor from the enzyme and partially or fully
reverse the inhibition.
 Noncompetitive inhibition: the inhibitor acts at a site on the
enzyme different from the active site (allosteric site). The
inhibition depends only on inhibitor concentration. Enzyme
inhibition cannot be reversed by increasing drug
concentration.
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Enzyme Inhibition
 Often rapid, reversible and relatively short
acting.
E.g. erythromycin and cyclosporin
NB erythromycin is a substrate and an
inhibitor of CYP 3A4
 May be prolonged due to long half- life of
drug.
E.g. amiodarone and S-Warfarin
NB amiodarone is an inhibitor of CYP2C9 but
not a substrate for this CYP
Extra-hepatic drug metabolism

 The liver is the main site but other sites may be
involved.
 These sites include the skin, the lung, the GI mucosal
cells, the microbial flora of distal parts of ileum and
large intestine. The kidney may play a role also.
 The metabolism is affected by the nature of the drug
and the route of administration.
 E.g. isoproterenol forms sulfate conjugate in the GI
mucosal cell after oral administration but forms
methylated metabolite after i.v. injection. Also
sulfasalazine is activated to absorbable form by the
microbial flora.
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EXCRETION OF DRUGS
Excretion is defined as the process where by

drugs or metabolites are irreversibly transferred from
internal to external environment through renal or non
renal route.
Excretion of unchanged or intact drug may be needed in
termination of its pharmacological action.
EXCRETION
 Urine is the main but NOT the only route.
 Glomerular filtration allows drugs of small MW to pass
into urine; reduced by plasma protein binding; only a

portion of plasma is filtered.
 Tubular secretion active carrier process for cations and
for anions; inhibited by probenicid.
 Passive re-absorption of lipid soluble drugs back into
the body across the tubule cells (non-ionized form).
Note: pH of the urine can be modified to control the drug
excretion rate. Alkaline urine reduce re-abosorption of
weak acid drug and vice verse.
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TYPES OF EXCRETION
1. RENAL EXCRETION
2. NON RENAL EXCRETION
 Biliary excretion.
 Pulmonary excretion.
 Salivary excretion.
 Mammary excretion.
 Skin / Dermal excretion.
 Gastrointestinal excretion.
 Genital excretion.
LONGITUDNAL SECTION OF KIDNEY

 The outer zone of the kidney is called
the cortex, and the inner region is
called the medulla.
 The nephrons are the basic functional
units, collectively responsible for the
removal of metabolic waste and the
maintenance of water and electrolyte
balance. Each kidney contains 1 to
1.5 million nephrons.
 The glomerulus of each nephron
starts in the cortex. Cortical nephrons
have short loops of Henle that
remain exclusively in the cortex;
medullary nephrons have long loops
of Henle that extend into the
medulla.
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ANATOMY OF NEPHRON
GLOMERULAR FILTRATION
 It Is non selective , unidirectional process

 Ionized or unionized drugs are filtered, except those
that are bound to plasma proteins.
 Driving force for GF is hydrostatic pressure of blood
flowing in capillaries.
 GLOMERULAR FILTRATION RATE:
Out of 25% of cardiac out put or 1.2 liters of
blood/min that goes to the kidney via renal artery only
10% or 120 to 130ml/min is filtered through glomeruli.
The rate being called as glomerular filtration rate
(GFR).e.g. creatinine, inulin.
68
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ACTIVE TUBULAR SECRETION
 This mainly occurs in proximal tubule.

 It is carrier mediated process which requires energy for
transportation of compounds against conc. Gradient
Two secretion mechanisms are identified.
System for secretion of organic acids/anions
E.g. Penicillin, salicylates etc uric acid secreted
System for organic base / cations
E.g. morphine
 Active secretion is Unaffected by change in pH and
protein
binding.
 Drug undergoes active secretion have excretion rate
values
greater than normal GFR e.g. Penicillin.
TUBULAR RE-ABSORPTION
 It occurs after the glomerular filtration of

drugs. It takes place all along the renal
tubules.
 Re-absorption of drugs indicated when the
excretion rate value are less than the GFR
130ml/min.e.g. Glucose
 TR can be active or passive processes.
 Re-absorption results in increased half life of
the drug.
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TUBULAR RE-ABSORPTION
Active Tubular Re-absorption:
Its commonly seen with endogenous substances or
nutrients that the body needs to conserve e.g. electrolytes,
glucose, vitamins.
Passive Tubular Re-absorption:
- It is common for many exogenous substances including drugs.
- The driving force is Conc. Gradient which is due to re-
absorption of water, sodium and inorganic ions.
- If a drug is neither excreted or re-absorbed its conc. in urine
will be 100 times that of free drug in plasma.
- only non-ionized form is reabsorbed.
- Affected by pH of the urine.
pH OF THE URINE
• It varies between 4.5 to 7.5

• It depends upon diet, drug intake and pathophysiology of
the patient .
• Acetazolamide and antacids produce alkaline urine, while
ascorbic acid makes it acidic.
• Relative amount of ionized ,unionized drug in the urine at
particular pH & % drug ionized at this pH can be given by “
HENDERSON-HESSELBACH” equation.
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HENDERSON-HESSELBACH
EQUATION
1- For weak acids
2- For weak bases
FACTORS AFFECTING RENAL

EXCRETION
 Physicochemical properties of drug

 Urine pH
 Blood flow to the kidney
 Biological factor
 Drug interaction
 Disease state
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PHYSICOCHEMICAL
PROPERTIES OF DRUG
 Molecular size
Drugs with Mol. wt <300, water soluble are excreted in

kidney. Mol. wt 300 to 500 Dalton are excreted both
through urine and bile.
 Binding characteristics of the drugs
Drugs that are bound to plasma proteins behave as

macromolecules and cannot be filtered through
glomerulus. Only free drug appears in glomerular
filtrate. Protein bound drug has long half lives.
BIOLOGICAL FACTORS
 Sex – Renal excretion is 10% lower in female

than in males.
 Age – The renal excretion in newborn is 30-
40 % less in comparison to adults.
 Old age – The GFR is reduced and tubular
function is altered which results in slow
excretion of drugs and prolonged half lives.
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DRUG INTERACTION
 Any drug interaction that result in alteration
of binding characteristics, renal blood flow,
active secretion, urine pH, and forced diuresis
would alter renal clearance of drug.
 Renal clearance of a drug that is highly bound
to plasma proteins can be increased after
being displaced with other drug e.g.
Gentamicin induced nephrotoxicity by
furosemide.
 Alkalinization of urine with bicarbonates
promotes the excretion of acidic drugs.
DISEASE STATE
 RENAL DYSFUNCTION
Greatly impairs the elimination of drugs
especially those that are primarily excreted by kidney.
Some of the reasons of renal failure are hypertension,
Diabetes, Pyelonephritis.
UREMIA
Characterized by Impaired GFR , accumulation of

fluids & protein metabolites, also impairs the excretion
of the drugs. Half life is increased resulting in drug
accumulation and increased toxicity.
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NON-RENAL ROUTE OF
DRUG EXCRETION
Various routes are
 Biliary Excretion
 Pulmonary Excretion
 Salivary Excretion
 Mammary Excretion
 Skin/dermal Excretion
 Gastrointestinal Excretion
 Genital Excretion
BILIARY EXCRETION
 Bile is secreted by hepatic cells of the liver. The flow is
steady 0.5 to 1ml /min.
 It is important in the digestion and absorption of fats.
 90% of bile acid is re-absorbed from intestine and
transported back to the liver for re-secretion.
 Compounds excreted by this route are sodium, potassium,
glucose, bilirubin, Glucuronide, sucrose, muco-proteins
e.t.c.
 The metabolites are more excreted in bile than parent drugs
due to increased polarity.
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BILIARY EXCRETION
 Phase-II reactions mainly glucuronidation and
conjugation with glutathione result in metabolites
with increased tendency for biliary excretion.
 Drugs excreted in the bile include chloromphenicol,
morphine and indomethacin.
 Glutathione conjugates have larger molecular weight
and so not observed in the urine. For a drug to be
excreted in bile must have polar groups like –COOH,
-SO3H.
 Clomiphene citrate, ovulation inducer is completely
removed from the body by BE.
THE ENTEROHEPATIC CIRCULATION
Some drugs which are excreted as glucuronides or glutathione conjugates are

hydrolyzed in the intestine to the parent drugs which are reabsorbed.
This phenomenon of drug cycling between the intestine & the liver is called
Enterohepatic circulation
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THE ENTEROHEPATIC CIRCULATION

 EC is important in conservation of Vitamins, Folic
acid and hormones.
 This process results in prolongation of half lives
of drugs like Carbenoxolone.
 Some drugs undergoing EC include are cardiac
glycosides, rifampicin and chlorpromazine.
 The principle of adsorption onto the resins in GIT
is used to treat pesticide poisoning by promoting
fecal excretion.
Pulmonary excretion
 Gaseous and volatile substances such as general
anesthetics (Halothane) are absorbed through
lungs by simple diffusion.
 Pulmonary blood flow, rate of respiration and
solubility of substance effect PE.
 Intact gaseous drugs are excreted but not
metabolites.
 Alcohol which has high solubility in blood and
tissues are excreted slowly by lungs.
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Salivary excretion
 The pH of saliva varies from 5.8 to 7.4.
 Unionized lipid soluble drugs are excreted
passively.
 The induced bitter taste in the mouth of a
patient is indication of salivary excretion.
 Compounds excreted in saliva include
Caffeine, Phenytoin, Theophylline.
Mammary excretion
 Milk consists of lactic secretions which are rich in fats
and proteins.
 0.5 to one litre of milk is secreted per day in lactating
mothers.
 Excretion of drug in milk is important as it gains entry
in breast feeding infants. pH of milk varies from 6.4
to 7.6.Free un-ionized and lipid soluble drugs diffuse
passively.
 Highly plasma bound drug like Diazepam is less
secreted in milk. Since milk contains proteins. Drugs
excreted can bind to it.
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Mammary excretion
 Amount of drug excreted in milk is less than
1% and fraction consumed by infant may be
too small to produce toxic effects.
 Some potent drugs like barbiturates and
morphine may induce toxicity.
 ADVERSE EFFECTS
 Discoloration of teeth with tetracycline and
jaundice due to interaction of bilirubin with
sulfonamides. Nicotine is secreted in the milk of
mothers who smoke.
Skin excretion
 Drugs excreted through skin via sweat
follows.
 Excretion of drugs through skin may
lead to urticaria and dermatitis.
 Compounds like benzoic acid, salicylic
acid, alcohol and heavy metals like lead,
mercury and arsenic are excreted in
sweat.
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GASTROINTESTINAL EXCRETION
 Excretion of drugs through GIT usually
occurs after parenteral administration.
 Water soluble and ionized from of
weakly acidic and basic drugs are
excreted in GIT.
 Example are nicotine and quinine are
excreted in stomach. Drugs excreted in
GIT are reabsorbed into systemic
circulation & undergo recycling.
EXCRETION PATHWAYS, TRANSPORT

MECHANISMS & DRUG EXCRETED.
Excretory Mechanism Drug Excreted

route
Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/
metabolites of MW< 500
Bile Active secretion Hydrophilic, unchanged drugs/
metabolites/ conjugates of MW >500
Lung Passive diffusion Gaseous &volatile, blood & tissue
insoluble drugs
Saliva Passive diffusion Free, unionized, lipophilic drugs. Some
Active transport polar drugs
Milk Passive diffusion Free, unionized, lipophilic drugs (basic)
Sweat/ Passive diffusion Free, unionized lipophilic drugs
skin
Intestine Passive diffusion Water soluble. Ionized drugs
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2. Intended learning outcomes of the course (ILOs)

c- Professional and practical skills

d- General and transferable skills

3. Teaching and learning methods

 Bioavailability: is the rate and extent of systemic

Pharmacokinetics involves the kinetics of drug

 The description of drug distribution and elimination

Hepatic portal blood during the

The dynamic relationships among the

Pharmacokinetics describes the

Fate of Drug in the Body

 The rate of drug release from the product, and the

Generalized plasma level-time curve

Rate-limiting Steps In Oral Drug Absorption

Rate-limiting Steps In Oral Drug

RATE-LIMITING STEPS IN ORAL

RATE-LIMITING STEPS IN ORAL

Schematic diagram showing the cells, cell

Oral Drug Absorption

The Cell Membrane

The Cell Membrane

Structure of Cell Membrane

Structure of Cell Membrane

Passage of Drugs across Cell

Drug transport and site of action

Types of Intestinal Membrane

Follow; 1- Passive Diffusion

Passive Diffusion of molecules

Follow; 1- Passive Diffusion

Follow; 1- Passive Diffusion

Follow; 1- Passive Diffusion

According to Fick’s Law of Diffusion,

 Where dQ/dt = rate of diffusion; D = diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Factors affecting passive diffusion

Follow; 5- The degree of ionization

When an acid or base is 50% ionised:

The non-ionized form is the absorbable

The ionized form is not able to get through

Factors affecting passive diffusion

Factors affecting passive diffusion

2.2- Facilitated diffusion

2.3- Carrier-Mediated Intestinal

Hypothetical carrier – mediated

2.1- Active transport

Follow 2.1- Active transport

Follow 2.1- Active transport

2.2- Facilitated Diffusion

Carrier – Mediated Intestinal

Multiple pathways for intestinal

Follow; 3- Vesicular transport

Factors Affecting Oral Drug

Follow; 1.1- Lipophilicity