Physiological Factors Affecting Oral Absorption By A S

Physiological Factors Affecting Oral Absorption By A. S. Adebayo, Ph. D.

Objective l 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

Blood-brain barrier v. Have effectively no pores in order to prevent many polar materials (often toxic materials) from entering the brain. v. Smaller lipid materials or lipid soluble materials, such as diethyl ether, halothane (used as general anesthetics) can easily enter the brain.

Renal tubules v. Relatively non-porous, only lipid compounds or non-ionized species (dependent of p. H and p. Ka) are reabsorbed. v. Placental barrier – find out ? ?

Blood capillaries and renal glomerular membranes v. 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. v. Especially useful in the kidney since it allows excretion of polar (drug and waste compounds) substances.

MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES l The apical cell membrane of the columnar absorption cell behaves as a ‘lipoidal’ membrane, interspersed by sub-microscopic water-filled channels or pores. l 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 l Most drug molecules are too large to pass through the aqueous channels. l The apical cell membrane of the g. i. -blood barrier allows the passage of lipid-soluble drugs in preference to lipid-insoluble drugs. l However, most drugs possess both lipophilic and hydrophilic entities that enable them to cross the barrier by the process of “Passive Diffusion”.

Passive Diffusion l Involves the movement of drug molecules from region of relatively high to low concentration without expenditure of energy. l 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). l The apical cell membrane plays only a passive role in the passive diffusion transport process.

Passive Diffusion (Cont. ) l The main factors determining the rate of drug transport are: ¡Physicochemical properties of the drug i. e. particle size, solubility, partition coefficient, p. H and p. Ka. ¡The nature of the membrane ¡The concentration gradient of drugs across the membrane.

Diagrammatic representation of g. i. absorption by passive diffusion G. I FLUID G. I. MEMBRANE BLOOD Drug in solution h Partition Diffusion Partition Drug in solution carried away by circulating blood

Fick’s Law of diffusion l Where d. Q/dt = rate of appearance of drug in the blodd at the site of absorption l D = the effective diffusion coefficient of the drug in the gi membrane l A = the surface area of g. i. membrane available for absorption by passive diffusion l k 1 = the apparent PC of drug between g. i. ‘membrane’ & the g. i. fluid.

Fick’s Law of diffusion (Cont. ) l Cg is the concentration of drug in solution in the g. i. fluid at the site of absorption l k 2 is the apparent PC of drug between the g. i. membrane & the blood l Cb is the concentration of drug in the blood at the site of absorption l h is the thickness of the g. i. membrane.

Fick’s Law of diffusion (Cont. ) l The drug in blood vessel is rapidly cleared away and the blood thus serves as a “sink” for absorbed drug as a result of: l Distribution in a large volume of blood i. e. systemic circulation l Distribution into body tissues and other fluids of distribution l Metabolism and excretion l Protein binding l 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 l. Active transport l. Facilitated transport

Active transport l Substances are transported against their concentration gradient (i. e. from low to high regions of concentration) across a cell membrane. l It is an energy-consuming process and involves active participation of the apical cell membrane of the columnar absorption cell.

Active transport (Cont. ) l 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. l 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. l 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. ) l Several carrier-mediated transport systems exist in the small intestine and each is highly selective with respect to the structure of substances it transports. l 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. l 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 l Differs from active transport in that it can not transport a substance against its concentration gradient l Does not require energy input. l Its driving force is the concentration gradient. l Another transport facilitator is required in addition to the carrier molecule.

Facilitated Transport of Vit. B 12 Carrier IF B 12 -IF Transported Vit. B 12

Receptor-mediated endocytosis l Process of ligand movement from the extracellular space to the inside of the cell by the interaction of the ligand with a specific cellsurface receptor. l The receptor binds the ligand at its surface l Internalizes it by means of coated pits and vesicles l Ultimately releases it into an acidic endosomal compartment.

Receptor-mediated endocytosis Cell membrane Free drug Released drug

Pinocytosis l Substance does not have to be in aqueous solution to be absorbed. l 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. l These vacuoles then cross the columnar absorption cells. l It is the main mechanism for the absorption of macromolecules such as proteins and waterinsoluble substances like vit. A, D, E and K.

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

Ion-pair transport l 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. l 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. l A suitable mechanism for the absorption of quaternary ammonium compounds and tetracyclines which are ionized over the entire g. i. p. H range. l Ion pair ≡ Organic anions + Organic cations = Neutral molecules (crossing lipoidal membrane by passive diffusion.

Characteristics of G. I physiology p. H Membrane BUCCAL approx 7 Thin ESOPHAGUS 5 -6 Very thick, no absorption - small Short - 1 -3 decompos ition, weak acid unionized Normal good small 30 - 40 minutes, reduced absorption no 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 STOMACH DUODENUM Blood Supply Good, fast absorption with low dose Surface Area small Transit Time Short unless controlled By-pass liver Yes

Factors that contribute to the intersubject variation in the g. i. p. H are l The general health of the individual l The presence of localized disease conditions (e. g. gastric & duodenal ulcers). l The type and amount of food ingested l 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 drugs Drug/dru Reported effect g group 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 The lower rate of absorption is not important this but total amount not chronically administered drug; concurrent food intake does reduced not alter the plasma concentration in patients on maintenance therapy Erythromyc Rate of absorption in (base & & amount absorbed stearate) 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 1 st pass metabolism, is increased by ≥ 50 %

Effect of Intestinal residence time l Controlled/sustained/prolonged release dosage forms as they pass through the entire length of the g. i. t. l Enteric coated dosage forms which release the drug only when in the small intestine l Drugs which dissolve slowly in the intestinal fluid l Drugs which are absorbed by intestinal carriermediated transport system.

Drugs affecting gastric emptying rate Decrease gastric emptying rate Increase gastric emptying rate Antihistamines Anticholinesterases Antimuscarenic drugs -Atropine -Propantheline Ganglion blocking drugs - Hexamethonium Opiod analgesics - Neostigmine - Physostigmine Dopamine antagonists - Domperidone - Metoclopramide - Diamorphine Iproniazid Reserpine - Buprenorphine Sodium bicarbonate - Meptazinol Sumatriptan - Morphine Phenothiazines Sympathomimetics - Isoprenaline

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