GASTROINTESTINAL

ABSORPTION

Subject Incharge
Muhammad Muaaz Munir
PH.D Scholar, MPhil, Pharm D, R.Ph.
 1. Oral Cavity

• Saliva is the main secretion of the oral cavity, and it has a pH of about 7.It contains
ptyalin (salivary amylase), which digests starches. About 1500 mL of saliva is
secreted per day.

• Mucin, a glycoprotein that lubricates food, is also secreted and may interact with
drugs.

• The oral cavity can be used for the buccal absorption of lipid-soluble drugs such as
fentanyl citrate and nitroglycerin, also formulated for sublingual routes.

• Recently, orally disintegrating tablets (ODTs), have become available.

2. Esophagus
• The esophagus connects the pharynx and the cardiac orifice of the stomach.
• The pH of the fluids in the esophagus is between 5 and 6.
• Tablets or capsules may lodge in this area, causing local irritation.
• Very little drug dissolution occurs in the esophagus.
 3. Stomach
• The fasting pH of the stomach is about 2–6.
• In the presence of food, the stomach pH is about 1.5–2, due to hydrochloric acid
secreted by parietal cells.
• Stomach acid secretion is stimulated by gastrin and histamine.
• Various gastric enzymes, such as pepsin, which initiates protein digestion, are
secreted into the gastric lumen to initiate digestion.
• The stomach is innervated by the vagus nerve for regulation of peristalsis ,gastric
secretions including acid and stomach emptying.
 4. Duodenum
• The duodenal pH is about 6–6.5, because of the presence of bicarbonate that
neutralizes the acidic chyme emptied from the stomach.
• The pH is optimum for enzymatic digestion of protein and peptide-containing
substances.
• Pancreatic juice containing enzymes is secreted into the duodenum from the bile duct.
• Trypsin, chymotrypsin and carboxypeptidase are involved in the hydrolysis of proteins
into amino acids.
• Amylase is involved in the digestion of carbohydrates.
• Pancreatic lipase secretion hydrolyzes fats into fatty acid.
 5. Jejunum

• The jejunum is the middle portion of the small intestine, between the duodenum and
the ileum.

• Digestion of protein and carbohydrates continues after addition of pancreatic juice

and bile in the duodenum.
 6. Ileum

• The ileum is the terminal part of the small intestine. This site also has fewer
contractions than the duodenum and may be blocked off by catheters with an
inflatable balloon and perfused for drug absorption studies.

• The pH is about 7, with the distal part as high as 8.

• Due to the presence of bicarbonate secretion, acid drugs will dissolve in the
ileum.
• Bile secretion helps dissolve fats and hydrophobic drugs.
 7. Colon
• Colon lacks villi and has limited drug absorption due to lack of large surface
area.
• PH of this region is 5.5 to 7.
• Drugs that absorbed in this region are best candidates for oral sustained release
dosage form.
• Aerobic and anaerobic microorganisms in colon also able to metabolize some drugs.
E.g. L-dopa and lactulose are metabolized by enteric bacteria
8. Rectum
• Rectum is about 15cm long ending at anus ,in the absence of fecal material,
rectum has small amount of fluid with pH of about 7.
• The small amount of fluid present in rectum has virtually no buffer capacity; so
dissolving drugs or even excipients can have determining effect.
 Oral Drug Absorption

Lipinski Rule of Five

It only help to predict adequate drug absorption and do not predict pharmacodynamic activity of drug
molecules.

Absorption and permeation of orally administered drugs occurs, if molecule have:

• Molecular weight ≤ 500
• Not more than 05 H-bond donor present in a molecule.
• Not more than 10 H-bond acceptors present in a molecule.
• An octanol-water partition coefficient, log P ≤ 5.0.
(Lipinski et al (1997, 2001))
 Factors affecting Drug absorption in GIT

Gastrointestinal Motility:

• Transit time of drug in GI tract depends on physicochemical and pharmacologic

properties of drug, types of dosage form and various physiologic factors.

• Movement of dug within GI tract depends on whether alimentary canal contains

recently ingested food or in fasted condition .
 Gastric emptying time
• As duodenum has greatest capacity for absorption ,a delay in gastric emptying time
for drug to reach the duodenum will slow the rate and possibly the extent of drug
absorption thereby prolonging the onset time of the drug.

• Liquids are generally emptied faster than digested solids from the stomach.

• Large particles, including tablets and capsules, are delayed from emptying for 3–6
hours by the presence of food in the stomach.

• Some drugs, such as penicillin, are unstable in acid and decompose if stomach
emptying is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa
during prolonged contact.
Indigestible solids empty very slowly, probably during the interdigestive phase, a
phase in which food is not present and the stomach is less motile but periodically
empties its content due to housekeeper wave contraction.

Factors that led to delay gastric emptying are:

✓ Consumption of meals high in fat

✓ Cold beverages
✓ Anticholinergic drugs
 Intestinal motility
• Normal peristaltic bring the drug particles in contact with the intestinal mucosal cells.

• Studies shown small intestine transient time (SITT) to be about 3 to 4 hrs.

• Thus a drug may take about 4 to 8 hours to pass through the stomach and small
intestine during the fasting state and 8 to 12 hours during fed state.

• Dietary fiber has the greatest effect on colonic transit.

• For modified-release or controlled-dosage forms, which slowly release the drug

over an extended period of time, the dosage form must stay within a certain
segment of the intestinal tract so that the drug contents are released and absorbed
before loss of the dosage form in the feces.
 Perfusion of the Gastrointestinal Tract
• The blood flow to the GI tract is important in carrying absorbed drug to the systemic
circulation, receives about 28% of the cardiac output and is increased after meals.

• Once the drug is absorbed from the small intestine, it goes via hepatic-portal vein to
the liver prior reaching the systemic circulation.

• Any decrease in blood flow, as in the case of congestive heart failure, will decrease
the rate of drug removal from the intestinal tract, thereby reducing the rate of drug
bioavailability (Benet et al, 1976).
 Absorption through the Lymphatic System
• Lipophilic drugs may be absorbed through the lacteal or lymphatic vessels under
the microvilli.
• Absorption of drugs through the lymphatic system bypasses the liver and avoids the
first-pass effect due to liver metabolism, because the lymphatic vessels drain into
the vena cava rather than the hepatic-portal vein.
• Drugs that can be significantly absorbed through the lymphatic system include
halofantrine, Bleomycin, certain testosterone derivatives, vitamin D-3, and the
pesticide DDT(dichloro-diphenyl-trichloroethane). (Yoshikawa et al, 1983, 1989,
Yanez et al, 2011).
 Effect of food on GI drug absorption

• The effects of food are not always predictable and can have clinically
significant
consequences. Some effects of food on the bioavailability from a drug product
include:

➢ Delay in gastric emptying

➢ Stimulation of bile flow
➢ A change in the pH of the GI tract
➢ A change in luminal metabolism of the drug substance
➢ Physical or chemical interaction of the meal with the drug product or substance

(US Food and Drug Administration, Guidance for Industry, December 2002)
• The absorption of some drugs, such as penicillin and tetracycline and certain
hydrophilic drugs, is decreased with food.

• Other drugs, particularly lipid- soluble drugs such as griseofulvin, metaxalone,

and metazalone, are better absorbed when given with food containing a high-fat
content.

• Some drugs, such as erythromycin, iron salts, aspirin and nonsteroidal anti-
inflammatory agents (NSAIDs) are irritating to the GI mucosa and are given with
food to reduce this irritation.
• Enteric-coated tablets may stay in the stomach for a longer period of time
because food delays stomach emptying. Thus, the enteric-coated tablet does not
reach the duodenum rapidly, delaying drug release and systemic drug absorption.
• Products that are used to control stomach acid secretion are usually taken before
meals, in anticipation of acid secretion stimulated by food.

• For example, Famotidine (Pepcid) and cimetidine (Tagamet) are taken before
meals to curb excessive acid production.

• Food can also affect the integrity of the dosage form, causing an alteration in
the release rate of the drug.

• For example, theophylline bioavailability from controlled-release tablets is much

more rapid when given in fed state rather than fasted state because of dosage
form failures, known as dose-dumping .
• Fluid volume tends to distend the stomach and speed up stomach emptying;
however, a large volume of nutrients with high caloric content supersedes that
faster rate and delays stomach emptying time.

• Reduction in drug absorption may be caused by several other factors such as

drug food interaction:

• For example, tetracycline hydrochloride absorption is reduced by milk and food

that contains calcium, due to tetracycline chelation.

• Generally, the bio-availability of drugs is better in patients in the fasted state and
with a large volume of water, a full glass (approximately 8 fluid oz or 250 mL)
 Physicochemical parameters
• Physicochemical factors affecting the drug absorption are following
1. Nature of drug
a. Form of drug – salt, ionic form
b. State - crystalline/ amorphous
c. Lipophilicity and Hydrophilicity
d. Partition coefficient
e. Drug pKa and pH
2. Degree of drug dissolution
3. Surface area and particle size
4. Bulk solubility, solubility in diffusion layer and degree of drug dissolution
5. Complexation
6. Adsorption
A. Salt form

• The salt form of parent compound has higher absorption regardless the pH of
dissolution media.

• Example: sodium/potassium salt of tolbutamide sodium has 5 times greater

absorption than salt free form in acidic media.
 B. Crystal form/ polymorphism
• Generally crystalline forms are more rigid and thermodynamically more stable than
amorphous form. Amorphous form dissolves more rapidly than corresponding crystalline
form.

Example: amorphous novobiocin is readily absorbed from aqueous suspension. Crystal

novobiocin is not absorbed (therapeutically ineffective).

• A change in crystal form may cause problems; Change in crystal structure may cause
cracking in a tablet, may cause inability for granules to be compressed or may cause
instabilities of dosage form.

• Example: Amorphous novobiocin slowly converts to more stable crystalline form and
become therapeutically ineffective.
Polymorphism:

Several drugs exist as more than one crystal form. Different crystals have different solubility
and physical properties. Different polymorphs show different dissolution rates and thereby
different bioavailability.

Example: chloramphenicol palmitate exist in three crystalline forms as:

A = stable polymorph
B = metastable polymorph (more soluble, rapid dissolution*)
C = unstable polymorph
Solvates:
• association of drug with solvent molecules to produce crystalline form known as
solvates.
• Drug + solvent = crystals.
• Greater is the solvation of crystal, the lower is solubility and dissolution rate.

Hydrates:
• drug associates with water molecules.
• Drug + water = crystal.
• Amorphous state is more soluble than hydrate. Less hydrated drug shows faster
dissolution.
• Example: anhydrous ampicillin is dissolved faster and absorbed more than in
trihydrate form.
C. Lipid solubility

• Some unionized drugs are not permeable through biological membrane – low lipid
solubility is the reason. Ex: penicillin, Gentamicin

• A drug must be lipid soluble as well, since the rate of absorption is related to oil/ water
partition coefficient (correlate water lipid solubility ).

𝑃𝑎𝑟𝑡𝑖𝑡𝑖𝑜𝑛 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡= 𝑃=𝑂𝑟𝑔𝑎𝑛𝑖c /𝐴𝑞𝑢𝑒𝑜𝑢𝑠

❑ The higher P value the more absorption.

 D. Dissolution
• It is a process by which the solid drug is dissolved into a fluid. It is the indicative of
the drug dissolution in aqueous biological fluid. Absorption rate is also dependent
upon dissolution rate following Noyes – Whitney equation.

• Dissolution is directly proportional to the effective surface area available to

dissolution media. Micronized drug (<5μm) gives higher blood levels than non-
micronized.

• Drugs with poor aqueous solubility are micronized to improve oral bioavailability.
Factors effecting dissolution:

• Effective surface area

• Solubility in diffusion layer
• Viscosity of diffusion fluid
• Presence of other substances
• Complexation
• Adsorption
 E. Surface area and particle size

• Example: Effect of particle size on the phenactin absorption.

- Smaller particle show quicker absorption

- Very small particle can clump together, addition of wetting agent (e.g. tween 80)
facilitates absorption.

- The intestinal fluids usually contain materials that can act as wetting agent.
 F. Bulk solubility, solubility in diffusion layer

Drug dissolution is considered to be diffusion controlled process through a

stagnant layer surrounding each solid particle in a solvent.

- Diffusion layer – immediate area surrounding drug particles added in a solvent

- Higher the drug in diffusion layer, more soluble and absorbable it would be.

Viscosity of dissolution media or liquid dosage form influence solubility

 G. Drug dissociation constant and pH

Weak acid:
• increasing pH of a weak acid increases ionization, Decreasing pH increases
unionized form.

Weak base:
• decreasing pH of a weak base increases ionization. Increasing pH favors
unionized form.
 H. Complexation

• Complexation of a drug with gastric fluid alter the rate of dissolution and extent
of
absorption. The complex forming agent may be component of gut, diet or of dosage
form. Complexation can favor or retard absorption.

• Example:
• i. Intestinal mucosa (mucin) + streptomycin = poorly absorbed complex (drug-gut comp.)
• ii. Calcium + tetracycline = poorly absorbed complex (drug – food interaction)
• Iii. Ibuprofen + cyclodextrin = enhanced absorption (drug-component of dosage form)
 I. Adsorption

• Adsorption of co-administered insoluble substances/ drugs leads to poor

solubility or bioavailability.

• Example:
• Charcoal (antidote in drug intoxication)
• Kaolin (antidiarrheal mixtures)
• Talc (in tablet as glidant)
 Double-Peak Phenomenon
• Observed after administration of a single dose to fasted patients

• Attributed to:
➢Variability in stomach emptying
➢Variable intestinal motility
➢Enterohepatic recycling
➢Failure of a tablet dosage form etc.
• For a drug with high water solubility, dissolution of drug occurs in stomach,
and partial emptying of drug into duodenum results in first absorption
peak. Second absorption peak is observed later due to delay in stomach
emptying

• For Example in cimetidine, phenomenon may be observed due to

variability in stomach emptying and intestinal flow rates after a single dose.
• Ranitidine produces double peak after both oral or parenteral (IV bolus)
administration

• Ranitidine is apparently concentrated in bile within the gallbladder from the

general circulation after IV administration

• Gallbladder contracts upon stimulation by food and bile containing drug is

released into the small intestine. The drug is then reabsorbed and
recycled(enterohepatic recycling)
• Tablet integrity may also be a factor in the production of a double peak.

• Mellinger and Bohorfoush compared a whole tablet and a crushed

tablet of dipyridamole in volunteers and showed that a tablet that does
not disintegrate or incompletely disintegrates may have delayed gastric
emptying, resulting in a second absorption peak
 Reference
• Applied Biopharmaceutics &pharmacokinetics by LEON SHARGEL Sixth Edition,
Page # 1-5, 321-336, 336-348, 363-370, 440-442.