PHARMACOKINETICS

PHM 201
BY

DR. ABDULHAKIM ABUBAKAR

FACULTY OF HEALTH SCIENCES

FUDMA
abdulhakimevuti@gmail.com

JUNE, 2024
 Pharmacokinetics is the study of absorption, distribution,
metabolism and excretion of drugs and their relationship to
pharmacologic response (what the body does to the drug).

It encompasses other parameters which include bioavailability, half-

life, volume of distribution and clearance.

Bioavailability describes the fraction (F) of a dose (D) of a drug that

enters systemic circulation.

Drugs administered IV have 100 % bioavailability (F= 1) while drugs

administered through other routes show incomplete bioavailability
(F<1).

Bioavailability is therefore determined by the degree of drug

absorption.
 Pharmacokinetics Cont’
The process whereby a drug initially enters body fluids is referred to as
absorption.

Before a drug can act within the body, it must be absorbed into the
blood stream which carries it to its site of action.

The rate of absorption is determined by the rate of transfer of the drug

across barriers between the sites of administration and action.

The route of administration largely determines the latent period

between administration and onset of action .
 Drugs given by mouth may be inactive for the following reasons:

 Enzymatic degradation of polypeptides within the lumen of the

GIT e.g. insulin, adrenocorticotropic hormone e.t.c
 Poor absorption from the GIT e.g. aminoglycoside antibiotics
 Inactivation :Compounds like propranolol, testosterone ,
aldosterone e.t.c are absorbed from the GIT but degraded during the
first passage through the liver before they can reach their sites of
action. This is referred to as ‘’first-pass effect or pre-systemic
elimination”.

In clinical practice, it is important to circumvent this first-pass effect

because some drugs are absorbed more rapidly from sublingual and
rectal routes than oral route . e.g. nitroglycerin tablet placed under
the tongue acts within 2-5 minutes .
 Drugs are also rapidly absorbed from the respiratory tract e.g.
gaseous and volatile GAs and from the bronchioles following acute
asthmatic attack e.g. inhalers.

The rate of absorption from SC or IM sites depends largely on two

factors; solubility of the drug and the blood flow through the
region.

Absorption from SC site by-passes the epidermal barrier but the

capillary blood flow is the major determinant of entry of drug into
circulation. The more the blood vessels in the subcutaneous area,
the larger the diameter of blood vessels and the greater the rate of
absorption.

Absorption from IM site is similar to SC since the epithelial barrier

is also by-passed.
 IV route completely by-passes absorption processes, since the drug
is introduced directly into the blood stream.

Irrespective of the route of administration, once a drug is absorbed

and circulating in the blood, the drug is said to be biologically
available or bioavailable and ready to produce effects.

Factors Affecting Oral Drug Absorption and its Bioavailability

 Physical properties of the drug (liquids, solids, crystalloids,
colloids , lipid or water solubility )
 Nature of the dosage form ( particle size, disintegration time,
type)
 Physiological factors
 Pharmacogenetic factors
 Disease state
• Physiological Factors
I. Ionization : It may be assumed for all practical purposes that the
mucosal lining of the GIT is impermeable to the ionized form of
weak organic acid or a weak organic base
The weakly acidic or basic organic drugs exist in two forms;
 An unionized component, predominantly lipid soluble and rapidly
absorbed (drugs cross the membrane which contains lipid)
 An ionized , water soluble component which is poorly absorbed.

II. pH-
 Acidic drugs are rapidly absorbed from the stomach because they
exist in the acidic medium of the stomach in an unionized form
which favours their absorption. e.g. salicylates and barbiturates
 Basic Drugs are not absorbed in the stomach until they reach the
alkaline environment of the small intestine in unionized form. The
actions of these drugs are delayed when administered orally. e.g.
pethidine and ephedrine.
 At the pH values found in the intestine, the strongly acidic or basic
drugs are highly ionized and hence are poorly absorbed.
Streptomycin, neomycin, mecamylamine, sulfaguanidine e.t.c. are
all strong bases and consequently have poor and irregular
absorption.

III. GI transit time: The presence of food, and the volume, viscosity
and tonicity of the gastric contents can influence drug absorption by
altering the gastric emptying time
 Rapid drug absorption occurs if the drug is given on empty stomach
 Increased peristaltic activity as in diarrhoea reduces drug absorption
 Anticholinergic drugs, which prolong gastric emptying time also
impairs drug absorption
 Food impairs or enhances drug absorption
• Food aids the absorption of :chloroquine, carbamazepine,
griseofulvin, nitofurantoin, riboflavin, spironolactone , lithium e.t.c

• Food hinders the absorption of: Ampicillin, tetracycline, aspirin,

digoxin, captopril, levodopa, INH, penicillin G, rifampicin e.t.c

• Presence of other agents : Vitamic C enhances iron absorption

from the GIT while phytates retard it. Absorption of fat soluble
vitamins is reduced by liquid paraffin. Calcium present in milk and
antacids forms insoluble complexes with tetracycline and reduces its
absorption

• IV. Enterohepatic circulation: Increases the bioavailability of a

drug . e.g . Phenolphthalein
V. Area of the absorbing surface and local circulation: Drugs can
be absorbed better from the small intestine than from stomach
because of the larger surface area of the former. Increased
vascularity can increase absorption.

VI. Metabolism of drug: Rapid degradation by the liver during the

First-pass effect can reduce absorption and bioavailability of drugs .
e.g. propranolol.

Disease States : Conditions like malabsorption syndrome,

achlorhydria, thyrotoxicosis, biliary obstruction and liver cirrhosis
affect drug absorption.
 Absorption of drugs from the GIT follows the laws of transfer of molecules
across the biological membrane.

Most drugs are absorbed by passive diffusion, a few by active transport or

carrier mediated transport and pinocytosis which is a mechanism for
transport of molecules across membranes.

 PASSIVE DIFFUSION: Bidirectional movement of molecules occurs

down the concentration gradient, without the input of energy. Drugs which
are lipid soluble are transferred across the membrane by simple or passive
diffusion after dissolving in the lipid of the cell membrane. Highly lipid
soluble drugs can thus be absorbed by this process regardless of the pH of
the medium.
 ACTIVE TRANSPORT : This is independent of the properties of the
membrane and requires energy (Na, K mg-activated ATPase). Many
inorganic ions such as Na, K, Ca and chloride need active transport
through the respective ion channels. Similarly, water soluble drugs of large
molecular size need active transport for their absorption.

A few synthetic drugs are also absorbed by active transport e.g alpha-
methyldopa, drugs related to steroids, glucose, and amino acids may also
be absorbed by active processes.

Majority of the drugs are however not absorbed by active transport.

Carrier-mediated transport is an active transport where a carrier

molecule combines with a drug to be transported to one membrane surface
and dissociates from it at another surface e.g. intestinal absorption of
calcium.
 Facilitated diffusion is a special example of carrier mediated transport, not
requiring an input of energy. It is highly selective and seems to operate in
the case of endogenous compounds whose rates of movement across
biological membranes by simple diffusion would otherwise be too slow e.g
absorption of cyanocobalamin from the gut.

 PINOCYTOSIS: Is the ability of the cell to engulf small droplets of

fluids or macromolecules but not particulate matter from its surroundings.
Aminoglycoside antibiotics enter the proximal tubule of the kidney by
this mechanism.
 t

DISTRIBUTION OF A DRUG
After absorption, a drug enters or passes through the various body
compartments. The total body area or body fluid to which a drug is
distributed is known as apparent volume of distribution ( Vd).

Compartments where drugs are distributed are:

 Total body water- Small water-soluble molecules e.g alcohol and
antipyrine.
 Extracellular space- Large water-soluble molecules e.g. mannitol
 Intravascular space- Very large, strongly protein-bound molecules e.g.
heparin.
 Body fat- Highly lipid soluble molecules e.g. DDT, thiopentone
 Bones- e.g. fluoride and lead
Every drug is distributed through the body based on its physicochemical
properties.

Drugs are also easily distributed through the highly perfused organs such
as liver, kidney and heart but distributed in small quantities through less
perfused tissues like muscles, fat and peripheral organs.
 The rate of passage of a drug through a membrane is dependent upon
properties such as:
 PH of the drug environment and the dissociation constant (PK) of the
drug, which is the PH at which the non-ionized and the ionized drugs are
equal
 Non-ionized, lipid soluble drugs (the vast majority) readily cross the
membrane and are distributed throughout the body; they have large
volumes of distribution
 Drugs which are highly protein bound remain largely within the vascular
compartment and have low volumes of distribution

Brain capillary endothelial cells have continuous tight junctions (blood

brain barrier); therefore drug penetration into the brain depends upon its
ability to cross the BBB.

The more lipophilic a drug is, the more likely it is to cross the BBB.

Drugs can also cross the placenta and may affect the developing fetus
• It is important to note that the volume of distribution can be affected
by diseases and individual variation.

• In some cases, dosing of drugs is based on lean body weight.

• In oedematous state, the volume of distribution is large, and the

concentration of drugs in the body will be small. In such a situation,
the amount of drug may have to be increased. It is necessary to note
that the dosage has to be reduced when oedema is corrected.

• Conversely, extremely dehydrated patients will have small volume

of distribution. In this case, a normal dose of a drug may lead to
higher concentration in body fluids. For such patients, dosage has to
be individualized.
 Factors that affect distribution of drugs in the body include :

 Plasma protein binding

 The rate of blood flow to various organs
 Cellular binding
 Concentration of fatty tissues
 BBB

Effects of Plasma Protein Binding on Drugs

I. Assists enteral absorption
II. Acts as temporary store, thereby prolonging action
III. Causes prolong levels of free drug
IV. Delays metabolic degradation
V. Delays excretion
VI. Diminishes penetration into the CNS
METABOLISM OR BIOTRANSFORMATION OF A DRUG
Metabolism refers to the modification of a drug by chemically
changing it to another compound, termed a metabolite.

Some drugs are administered as inactive ‘prodrugs’ which are

metabolized into the pharmacologically active form.

Metabolism of drugs usually tends to make the less polar, lipid

soluble substances more polar and water soluble, thus facilitating
their excretion by kidneys.

Metabolism of drugs occur predominantly in the liver, although

some other tissues and organs e.g. the lungs can carry out varying
degree of drug metabolism.
 Drug metabolism has two important effects ;
I. The drug is made more hydrophilic
II. The metabolites are usually less active than the parent drug.
However, this is not always so, and sometimes the metabolites are
as active or more active than the original drug.

For example, diazepam is metabolized to nordiazepam and

oxazepam, both of which are active.

Some drugs are administered as ‘prodrugs’, in an inactive or less

active form to promote absorption, by-pass potential destruction by
stomach enzymes or to reduce exposure to other moieties. Such
prodrugs remain inactive until they are metabolized in the body to
the active form.

For example, levodopa is metabolized to active dopamine, while

methyldopa is metabolized to more active α-methylnoradrenaline.
• Majority of drugs , however, are metabolized by the enzymes
resulting in their activation, inactivation and modification. The
reactions which bring about this changes are;
I. Oxidation
II. Reduction
III. Hydrolysis
IV. Conjugation or synthesis

Based on the reactions above, drug metabolism is divided into two

phases: Phase I (Functionalization) and phase II (Conjugation)

Phase 1 or Functionalization: Oxidation, reduction and hydrolysis

introduce polar groups such as hydroxyl, amino, sulfhydryl and
carboxy into drugs which are consequently made water soluble and
pharmacologically less active
Phase I reaction prepares the drug for phase II
 Phase II or Conjugation
This is a synthetic process by which a drug or its metabolites is
combined with an endogenous substance, resulting in various
conjugates such as glucuronides, sulphates, methylated and amino
acid conjugates

Conjugation results in inactivation of the compound. After such

inactivation, large molecules are eliminated in the bile while
smaller molecules are excreted in the urine
Phase II or Conjugation reactions are;
I. Glucuronic acid conjugation or glucuronidation
II. Sulphate conjugation or sulphation
III. Amino acid Conjugation
IV. Glutathione Conjugation
V. Acetylation
VI. Methylation
 Factors Affecting Drug Metabolism

I. Animal Species and strain

II. Age and sex
III. Genetic endowment
IV. Diet
V. Route and duration of drug administration
VI. Simultaneous administration of other drugs( enzyme induction and
inhibition)
VII. Presence of disease
DRUG EXCRETION
Renal excretion is ultimately responsible for elimination of most of
the drugs and/or their metabolites

The main route of excretion of drugs and their metabolites is the

urine followed by the faeces (for unabsorbed orally administered
drugs)

Some gaseous or volatile general anaesthetics are eliminated

through the lungs

Drugs may be removed through secretions, such as sweat and milk

Some drugs excreted into the bile are reabsorbed from the intestine
(enterohepatic circulation) thus prolonging the effects of such
drugs
 Lipid- soluble drugs are not readily excreted until they are metabolized to
more polar compounds.

The processes which contribute to the elimination of drugs from the urine are;
 Glomerular filtration
 Active tubular secretion
 Passive tubular reabsorption

Changes in renal function generally affect all three processes to a similar

extent.

Unionized drugs which are well absorbed are filtered at the glomerulus, but
they can diffuse back from the lumen of the renal tubule into the cells lining
the tubules. Thus, only small amount of drugs appear in the urine.

Ionized drugs which are poorly absorbed are excreted almost entirely by GF
and are not reabsorbed.
 In neonates, renal function is low compared with body mass but matures rapidly
within the first few months after birth.

During adulthood, there is a low decline in renal function , approximately 1%

yearly.

In elderly patients, a substantial degree of functional renal impairment may be

present
Other Sites of Drug Excretion and Examples of Drugs They Excrete
 Lungs: Volatile GAs , alcohol and paraldehyde
 Skin: Arsenic, mercury e.t.c
 Bile: Novobiocin, erythromycin, phenolphthaleine (undergo enterohepatic
circulation)
 Intestines: cascara, senna, heavy metals e.t.c.
 Saliva: iodide, lead sulfide (blue lines on the gums)
 Breast milk: Diazepam, lithium, cimetidine, antineoplastic drugs, antithyroid
drugs, Tetracyclines, INH, chloramphenicol, erythromycin estolate, phenyl-
butazone, reserpine, clonidine, sulphonamides e.t.c.
Biological Half-Life
It is the time taken for one-half (50%) of the administered concentration of
a drug to be removed from the body.

It gives an idea of how long it takes a patient to reach steady state on a

constant dosage regimen, for instance, one half-life (50%) of steady state,
two half-life (75%), three half-life (87.5%) and four half-life (93.75%)
steady state. 3 or 4 Half-lives are required to reach steady state

It gives an idea how long it takes a drug to be eliminated from the body e.g.
50% of drug remain after 1 half-life, 25% remain after 2 half-life, 12.5%
remain after 3 half-life and 6.25% after 4 half-life. About 4 half-lives are
needed to have appreciable elimination from the body. This is important in
drug toxicity

It may also be used to estimate an appropriate dosing interval