Physiological Factors Affecting Oral Absorption

By

A. S. Adebayo, Ph.D.

Objective

At the end of this topic, we should be able to:

Understand the physiological factors which affect the oral absorption of drug products

Apply the knowledge to optimization of

patient’s benefit from administered drug

Overall picture of drug absorption, distribution, and elimination

Davson-Danielli Model

Simplified Model of Membrane

Examples of some membrane types

Have effectively no pores in order to prevent many polar materials (often toxic materials) from entering the brain.

Smaller lipid materials or lipid soluble materials, such as diethyl ether, halothane (used as general anesthetics) can easily enter the brain.

Blood-brain barrier

Renal tubules

Relatively non-porous, only lipid compounds or non-ionized species (dependent of pH and pKa) are reabsorbed.

Placental barrier – find out ??

Blood capillaries and renal glomerular membranes

Quite porous, allowing non-polar and polar molecules (up to a fairly large size, just below that of albumin, (M.Wt 69,000) to pass through.

Especially useful in the kidney since it allows excretion of polar (drug and waste compounds) substances.

MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES

The apical cell membrane of the columnar absorption cell behaves as a ‘lipoidal’ membrane, interspersed by sub-microscopic water-filled channels or pores.

Water soluble substances of small molecular size (radius 0.4 nm) such as urea are absorbed by simple diffusion through the water-filled channels.

MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES

Most drug molecules are too large to pass through the aqueous channels.

The apical cell membrane of the g.i.-blood barrier allows the passage of lipid-soluble drugs in preference to lipid-insoluble drugs.

However, most drugs possess both lipophilic and hydrophilic entities that enable them to cross the barrier by the process of “Passive Diffusion”.

Passive Diffusion Involves the movement of drug molecules from

region of relatively high to low concentration without expenditure of energy.

Movement continues until equilibrium has been reached between both sides of the membrane

the equilibrium tend to be achieved faster with highly permeable (i.e. lipid soluble drugs) and when membrane has a large surface area (e.g. intestine vs stomach or duodenum).

The apical cell membrane plays only a passive role in the passive diffusion transport process.

Passive Diffusion (Cont.)

The main factors determining the rate of drug transport are:Physicochemical properties of the drug i.e.

particle size, solubility, partition coefficient, pH and pKa.

The nature of the membrane

The concentration gradient of drugs across the membrane.

Diagrammatic representation of g.i. absorption by passive diffusion

h

Partition PartitionDiffusion

Drug in solution

Drug in solution carried away by circulating blood

G.I FLUID

BLOODG.I. MEMBRANE

Fick’s Law of diffusion

Where dQ/dt = rate of appearance of drug in the blodd at the site of absorption

D = the effective diffusion coefficient of the drug in the gi membrane

A = the surface area of g.i. membrane available for absorption by passive diffusion

k1 = the apparent PC of drug between g.i. ‘membrane’ & the g.i. fluid.

h

CkCkDA

dt

dQ bg )( 21

fluid g.i.in drug ofion concentrat

interface membranefluid/ g.i.at membrane theinside drug ofion concentrat the1 k

Fick’s Law of diffusion (Cont.)

Cg is the concentration of drug in solution in the g.i. fluid at the site of absorption

k2 is the apparent PC of drug between the g.i. membrane & the blood

Cb is the concentration of drug in the blood at the site of absorption

h is the thickness of the g.i. membrane.

Fick’s Law of diffusion (Cont.)

The drug in blood vessel is rapidly cleared away and the blood thus serves as a “sink” for absorbed drug as a result of:

Distribution in a large volume of blood i.e. systemic circulation

Distribution into body tissues and other fluids of distribution

Metabolism and excretion

Protein binding

Hence, a large concentration gradient is always maintained across the g.i. membrane during absorption process and this conc. gradient becomes the sole driving force behind drug absorption by passive diffusion mechanism.

Specialized Transport Mechanisms

Active transport

Facilitated transport

Active transport

Substances are transported against their concentration gradient (i.e. from low to high regions of concentration) across a cell membrane.

It is an energy-consuming process and involves active participation of the apical cell membrane of the columnar absorption cell.

Active transport (Cont.)

Drug molecule or ion forms a complex with a “carrier” which, may be an enzyme or some other components of the cell membrane, to form a “drug-carrier” complex.

This complex then moves across the membrane, liberates the drug on the other side and the carrier returns to the original state and surface to repeat the process.

As for g.i absorption, transfer occurs only in the direction of g.i. lumen to the blood i.e. not normally against the conc. gradient, the carrier being generally a ‘one-way’ transport system.

Active transport (Cont.)

Several carrier-mediated transport systems exist in the small intestine and each is highly selective with respect to the structure of substances it transports.

Drugs resembling such substances can be transported by the same carrier mechanism. E.g. Levodopa resembles tyrosine and phenylalanine and is

absorbed by the same mechanism.

Active transport proceeds at a rate directly proportional to the concentration of the absorbable species only at low concentration the mechanism becomes saturated at high concentrations.

Illustration of Specialized Transport

Facilitated transport

Differs from active transport in that it can not transport a substance against its concentration gradient

Does not require energy input.

Its driving force is the concentration gradient.

Another transport facilitator is required in addition to the carrier molecule.

Facilitated Transport of Vit. B12

Carrier

B12

IF

B12-IFTransported Vit. B12

Receptor-mediated endocytosisProcess of ligand movement from the extracellular

space to the inside of the cell by the interaction of the ligand with a specific cell-surface receptor.

The receptor binds the ligand at its surface

Internalizes it by means of coated pits and vesicles

Ultimately releases it into an acidic endosomal compartment.

Receptor-mediated endocytosis

Cell membrane

Free drug

Released drug

PinocytosisSubstance does not have to be in aqueous

solution to be absorbed.

Like phagocytosis, it involves invagination of the material by the apical cell membrane of the columnar absorption cell lining the g.i.t. to form vacuoles containing the material.

These vacuoles then cross the columnar absorption cells.

It is the main mechanism for the absorption of macromolecules such as proteins and water-insoluble substances like vit. A, D, E and K.

Convective absorption

By this mechanism, very small molecules such as water, urea and low molecular weight sugars and organic electrolytes are able to cross cell membranes through aqueous filled channels or pores.

The effective radii of these channels are small (≈ 0.4 nm) such that the mechanism is of little significance in the absorption of large, water-insoluble drug molecules or ions.

It is the mechanism involved in the renal excretion of drugs and the uptake of drugs into the liver.

Ion-pair transport In this mechanism, some ionized drug species interact

with endogeneous organic ions of opposite charge to form absorbable neutral specie i.e. an ion-pair.

The charges are “buried” in ion pair and the complex can now partition into the lipoidal cell membrane lining the g.i.t. and be absorbed by passive diffusion.

A suitable mechanism for the absorption of quaternary ammonium compounds and tetracyclines which are ionized over the entire g.i. pH range.

Ion pair ≡ Organic anions + Organic cations = Neutral molecules (crossing lipoidal membrane by passive diffusion.

Characteristics of G.I physiology

pH Membrane Blood Supply Surface Area Transit Time By-pass liver

BUCCAL approx 7 Thin Good, fast absorption with low

dose

small Short unless controlled

Yes

ESOPHAGUS 5 - 6 Very thick, no absorption

- small Short -

STOMACH 1 - 3 decompos

ition, weak acid unionized

Normal good small 30 - 40 minutes, reduced

absorption

no

DUODENUM 6 - 6.5 bile duct,

surfactant properties

Normal good very large very short (6" long),

window effect

no

SMALL INTESTI

NE

7 – 8 Normal good very large 10 - 14 ft, 80 cm 2 /cm

about 3 hours no

LARGE INTESTI

NE

5.5 - 7 - good not very large 4 - 5 ft

long, up to 24 hr

lower colon, rectum

yes

Factors that contribute to the inter-subject variation in the g.i. pH are

The general health of the individual

The presence of localized disease conditions (e.g. gastric & duodenal ulcers).

The type and amount of food ingested

Drug therapy (co-administered drugs)

Gastric emptying and motility

Dependence of Peak Acetaminophen Plasma Concentration as a Function of Stomach Emptying Half-life

Table 2 - Factors Affecting Gastric Emptying

Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to

empty more slowly than liquids

Type of Meal

Fatty food Decrease

Carbohydrate Decrease

Temperature of Food Increase in temperature, increase in emptying rate

Body Position Lying on the left side decreases emptying rate. Standing versus lying

(delayed)

Drugs

Anticholinergics (e.g. atropine) Decrease

Narcotic (e.g. morphine) Decrease

Analgesic (e.g. aspirin) Decrease

Food

Figure 2 - Showing the Effect of Fasting versus Fed state on Propranolol Concentrations

Effect of food on absorption of some drugsDrug/drug group

Reported effect Comments

Reduced absorption

Atenolol Food decreases the extent of absorption

Reduction of about 20% has been reported

Captopril Food decreases the extent of absorption

Reduction is 35.5 to 40% and may alter therapeutic effect

Digoxin Absorption delayed but total amount not reduced

The lower rate of absorption is not important this chronically administered drug; concurrent food intake does not alter the plasma concentration in patients on maintenance therapy

Erythromycin (base & stearate)

Rate of absorption & amount absorbed are reduced

Extent of absorption of the base and stearate is reduced in fed state because of acid hydrolysis. Extent of absorption is higher in the fed state for the more stable estolate derivative.

Effect of food on absorption of some drugs (Cont.)

Increased absorption

Dicumarol Extent of absorption is increase by food

Griseofulvin Absorption increased by concurrent ingestion of fatty meal

May be due to dissolution in fat components and absorption through fat uptake mechanisms

Phenytoin Food appears to increase the rate & extent of absorption

Changes in extent of absorption can be dangerous because of saturable hepatic metabolism.

Propranolol, metoprolol, labetalol & hydralazine

Absorption greater in fed than in fasted state

The low system availability, due to extensive 1st pass metabolism, is increased by ≥ 50 %

Effect of Intestinal residence timeControlled/sustained/prolonged release dosage

forms as they pass through the entire length of the g.i.t.

Enteric coated dosage forms which release the drug only when in the small intestine

Drugs which dissolve slowly in the intestinal fluid

Drugs which are absorbed by intestinal carrier-mediated transport system.

Drugs affecting gastric emptying rateDecrease gastric emptying rate Increase gastric emptying rate

Antihistamines Anticholinesterases

Antimuscarenic drugs - Neostigmine

-Atropine -Propantheline

- Physostigmine

Ganglion blocking drugs Dopamine antagonists

- Hexamethonium - Domperidone

Opiod analgesics - Metoclopramide

- Diamorphine IproniazidReserpine

- Buprenorphine Sodium bicarbonate

- Meptazinol Sumatriptan

- Morphine

Phenothiazines

Sympathomimetics

- Isoprenaline

***END OF PRESENTATION***

QUESTIONS/DISCUSSION