Physiological Factors Affecting Oral Absorption

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

2. 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

3. Overall picture of drug absorption, distribution, and elimination

4. Davson-Danielli Model

5. Simplified Model of Membrane

6. Examples of some membrane types

7. Blood-brain barrier • 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.

8. Renal tubules • Relatively non-porous, only lipid compounds or non-ionized species (dependent of pH and pKa) are reabsorbed. • Placental barrier – find out ??

9. 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.

10. 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.

11. 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”.

12. 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.

13. 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.

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

15. 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. Fick’s Law of diffusion

16. 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.

17. 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.

18. Specialized Transport Mechanisms • Active transport • Facilitated transport

19. 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.

20. 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.

21. 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.

22. Illustration of Specialized Transport

23. 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.

24. B12 Carrier IF Transported Vit. B12 B12-IF Facilitated Transport of Vit. B12

25. Receptor-mediated endocytosis • Process 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.

26. Cell membrane Free drug Released drug Receptor-mediated endocytosis

27. Pinocytosis • Substance 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.

28. 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.

29. 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.

30. Characteristics of G.I physiology

31. 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)

32. Gastric emptying and motility Dependence of Peak Acetaminophen Plasma Concentration as a Function of Stomach Emptying Half-life

33. Table 2 - Factors Affecting Gastric Emptying

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

35. Effect of food on absorption of some drugs

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

37. Effect of Intestinal residence time • Controlled/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.

38. Drugs affecting gastric emptying rate

39. ***END OF PRESENTATION*** QUESTIONS/DISCUSSION