Mechanism of drug absorption in git

Drug absorption

1. By A njita Khadka Mechanism of Drug Absorption in GIT

2. Drug Absorption Definition: The process of movement of unchanged drug from the site of administration to systemic circulation . T here always exist a correlation between the plasma concentration of a drug and the therapeutic response . So absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement i.e. Plasma.

3. Fig: plots showing significance of rate and extent of absorption in drug therapy

4. Basic structure of functional cell membrane

5. Mechanism of drug absorption Transcellular /intracellular transport 1.Passive transport process Passive diffusion Pore transport Ion-pair transport Facilitated or carrier mediated diffusion 2. Active transport process Primary active transport Secondary active transport: S ymport (co-transport) and Antiport (counter-transport)

6. B. Paracellular /Intercellular Transport: 1. Permeation through tight junctions of epithelial cells. 2. Persorption C. Vesicular or corpuscular Transport ( Endocytosis ): 1. Pinocytosis 2.Phagocytosis

7. Transcellular /intracellular Transport: Passage of drugs across the GI epithelium. Passive Transport process: do not require energy other than that of molecular motion (Brownian motion) to pass through the lipid bilayer . Passive diffusion: Also called as Non-ionic diffusion. Major process for absorption of more than 90% of the drugs. Driving force: concentration or electrochemical gradient. It is defined as the difference in the drug concentration on either side of the membrane.

8. no energy source required. No carrier is needed. Water soluble drug (ionized or Polar): readily absorbed via aqueous channels or pores in the cell membrane. Lipid soluble drug (non-ionized or non polar): readily absorbed via cell membrane itself. Depends on lipid solubility. Depends on pka of drug-pH of medium.

9. Passive diffusion is best expressed by Fick’s first law of diffusion. Fick’s first law of diffusion states that the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the concentration gradient across the membrane. Mathematically, Where, dQ / dt = rate of drug diffusion D = diffusion coefficient A = surface area of the absorbing membrane for drug diffusion Km/w = Partition coefficient ( Cgit -C) = concentration gradient h = thickness of membrane

10. Certain characteristics of passive diffusion: Downhill transport. Process is energy independent and non saturable . Greater the surface area & lesser the thickness of the membrane= faster the diffusion & more rapid the rate of drug absorption from intestine than from stomach. Equlibrium is attained when the concentration on either side of the membrane becomes equal. Greater the membrane/ water partition coefficient of drug = faster the absorption

11. Certain characteristics of passive diffusion contd.. Only non- ionised form is absorbable. The rate of transfer of unionised species is 3 -4 times the rate for ionised drugs . Weak acids: best absorbed in stomach ( Aspirin,Phenobarbitone , Penicillin V) Weak bases: best absorbed in intestine (Atropine, Ephedrine, Chloroquine )

12. b. Pore transport Also called as convective transport, bulk flow or filtration. Transport of molecules into the cell through the protein channels present in the cell membrane. The driving force is constituted by the hydrostatic or the osmotic pressure differences across the membrane. Important in the absorption of low molecular weight (<100 dalton ), low molecular size (smaller than the diameter of the pore) and generally water-soluble drugs through narrow, aqueous filled channels or pores in the membrane structure. For example: Urea, water and sugars

13. c. Ion-pair transport Transport of drugs like quaternary ammonium compounds and sulphonic acids, which ionise under all pH conditions. Despite their low O/W partition coefficient values, such agents penetrate the membrane by forming reversible neutral complexes with endogenous ions of the GIT like mucin . Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion Propranolol , a basic drug that forms an ion pair with oleic acid, absorbed by this mechanism.

14. d. Facilitated/carrier mediated transport Mechanism involves driving force = concentration gradient No energy expenditure is involved, the process is not inhibited by metabolic poisons that interfere with energy production. Limited importance in the absorption of drugs. For e.g. such a transport system include entry of glucose into RBCs and intestinal absorption of vitamins B1 & B2. A classic example of passive facilitated diffusion is the GI absorption of vitamin B12. An intrinsic factor , a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B12, then transported across the intestinal membrane by a carrier system.

15. 2. Active transport Process Requires energy in the form of ATP Against concentration gradient Uphill transport; without any regard for equilibrium. Faster than passive diffusion Inhibited by metabolic poisons that interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen. Useful in cancer chemotherapy: 5-fluorouracil, 5-bromouracil Important in renal and biliary excretion of many drugs and metabolites & secretion of certain aciids out of the CNS.

16. Active transport Process Further subdivided into: a . Primary active transport : direct ATP requirement ( e.g. absorption of glucose); carrier proteins involved in primary active transport are of 2 types: Ion transporters : responsible for transporting ions in or out of cells (e.g. ATP driven ion pump called proton pump implicated in acidification of intracellular compartments); Organic anion transporter aids absorption of Pravastatin and Atorvastatin ; Organic cation transporter aids absorption of Diphenhydramine . ATP binding transporters : transport small foreign molecules ( drugs and toxins) especially out of cells i.e. exsorption e.g. p-glycoprotein; responsible for pumping hydrophobic drugs like anticancer drugs out of cells. (present in brains)

17. b. Secondary active transport: no direct requirement of ATP (takes advantage of previously existing concentration gradient) Symport (co-transport): involves movement of both molecules in the same direction e.g. Na+ concentration gradient to move glucose against its concentration gradient ; H+ coupled peptide transporter (PEPT1) implicated in the intestinal absorption of peptide like drugs such as β - lactam antibiotics. Antiport (counter-transport): involves movement of molecules in the opposite direction e.g. expulsion of H+ ions using the Na+ gradient in the kidneys.

18. B. Paracellular /Intercellular transport Transport of drugs through the junctions between the GI epithelial cells. Paracellular transport mechanisms involved in drug absorption: Permeation through tight junctions of epithelial cells: occurs through openings which are little bigger than the aqueous pores e.g. insulin, cardiac glycosides Persorption : through temporary openings formed by shedding of 2 neighbouring epithelial cells into the lumen.

19. C. Vesicular/ Corpuscular transport ( Endocytosis ): Involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle which is then picnched -off intracellularly . Responsible for the cellular uptake of macromolecular nutrients like fats & starch, oil soluble vitamins like A, D, E & K, water soluble vitamin like B12 & drugs like insulin. Bypass first pass hepatic metabolism Involves 3 processes: Phagocytosis , Pinocytosis and Transcytosis Transcytosis : Phenomenon in which an endocytic vesicle is transferred from one extracellular compartment to another.

20. Phagocytosis (cell eating): Adsorptive uptake of solid particulates, macromolecules.

21. Pinocytosis (cell drinking): Uptake of fluid solute. Orally administered Sabin Polio vaccine, lagre protein molecules, botulism toxin, oil, soluble vitamins etc absorbed by this mechanism

22. Combined Absorption Mechanisms Absorbed by more than just one mechanism. For e.g. cardiac glycosides (absorbed both passively as well as by active transport) Vitamin B12 (absorbed by passive diffusion, facilitated diffusion as well as endocytosis )

23. Conclusion Passive diffusion: most drugs having high lipophilicity & MW in the range 100-400 dalton are absorbed. Pore transport: water soluble drugs of MW less than 100 dalton are absorbed. Ion-pair transport: drugs that ionise at all pH conditions absorbed after complexing with oppositely charged ions are absorbed. Carrier-mediated transport: structure-specific drugs with affinity for carriers transported from specific sites are absorbed. Endocytosis : macromolecular nutrients and drugs as solid particles or oily droplets are absorbed.