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Mechanisms of Drug Absorption Across Biological Membranes

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TRANSPORT ACROSS BIOMEMBRANES
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES ,[object Object],[object Object],[object Object]
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES ,[object Object],[object Object],[object Object],[object Object]
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES ,[object Object],[object Object],[object Object]
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
From: Hunter J, Hirst BH. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Advanced Drug Delivery Reviews 25:129-157, 1997.
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES – Paracellular Pathway ,[object Object],[object Object],[object Object],[object Object],[object Object]
MECHANISMS OF DRUG TRANSPORT ACROSS BIOMEMBRANES Convective absorption ,[object Object],[object Object],[object Object],[object Object]
Trancellular Pathway Passive Diffusion ,[object Object],[object Object],[object Object]
Trancellular Pathway Passive Diffusion ,[object Object],[object Object],[object Object],[object Object]
Diagrammatic representation of g.i. absorption by passive diffusion h Partition Partition Diffusion Drug in solution Drug in solution carried away by circulating blood G.I FLUID BLOOD G.I. MEMBRANE
Fick’s Law of diffusion ,[object Object],[object Object],[object Object],[object Object]
Fick’s Law of diffusion (Cont.) ,[object Object],[object Object],[object Object],[object Object]
Fick’s Law of diffusion (Cont.) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Specialized Transport Mechanisms ,[object Object],[object Object],[object Object],[object Object],[object Object]
Specialized Transport Mechanisms Active transport ,[object Object],[object Object],[object Object]
Specialized Transport Mechanisms Active transport ,[object Object],[object Object],[object Object]
Proposed Model for Carrier-Mediated Transport
Membrane Transporters and Their Substrates Transporter Substrates Amino acid transporters baclofen, cyclosporin, L-dopa, gabapentin, methyldopa Peptide transporters  -lactam antibiotics, ACE inhibitors, (hPEPT1, HPT1) cephalexin, cyclosporin, methyldopa Nucleoside transporters zidovudine, zalcitabine, dipyridamole (CNT1, CNT2) Organic anion transporters ceftriaxone, benzoic acid, methotrexate (OATP1, OATP3, OATP8) pravastatin Organic cation transporters thiamine, desipramine, quinidine, (OCT1,OCT2) midazolam, verapamil Bile acid transporters chlorambucil, thyroxine (IBAT/ISBT)
Illustration of Specialized Transport
Specialized Transport Mechanisms Facilitated Transport ,[object Object],[object Object],[object Object],[object Object]
Facilitated Transport of Vit. B 12 Carrier B12 IF B12-IF Transported Vit. B12
Transcellular Pathway Endocytosis ,[object Object],[object Object],[object Object],[object Object]
Transcellular Pathway Endocytosis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Transcellular Pathway Pinocytosis ,[object Object],[object Object],[object Object],[object Object]
Receptor-mediated endocytosis ,[object Object],[object Object],[object Object],[object Object]
Receptor-mediated Endocytosis ,[object Object],[object Object]
Receptor-mediated endocytosis Cell membrane Free drug Released drug
Phagocytosis ,[object Object],[object Object],[object Object]
Transcytosis ,[object Object]
Ion-pair transport ,[object Object],[object Object],[object Object],[object Object]
Efflux of Drugs from the Intestine ,[object Object],[object Object],[object Object],[object Object],[object Object]
Consequence of the Efflux Transporter P-glycoprotein 1) Limited drug absorption enterocyte pgp Gut lumen 2) Enhanced drug elimination Proximal tubule cells Tubule lumen hepatocytes bile 3) Limited distribution Endothelial cells capillary Brain or testes syncytiotrophoblast Maternal blood lymphocyte Adapted from: Fromm MF. Trends in Pharmacol Sci 25:423, 2004

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Mechanisms of Drug Absorption Across Biological Membranes

  • 2.
  • 3.
  • 4.
  • 5.
  • 6. From: Hunter J, Hirst BH. Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption. Advanced Drug Delivery Reviews 25:129-157, 1997.
  • 7.
  • 8.
  • 9.
  • 10.
  • 11. Diagrammatic representation of g.i. absorption by passive diffusion h Partition Partition Diffusion Drug in solution Drug in solution carried away by circulating blood G.I FLUID BLOOD G.I. MEMBRANE
  • 12.
  • 13.
  • 14.
  • 15.
  • 16.
  • 17.
  • 18. Proposed Model for Carrier-Mediated Transport
  • 19. Membrane Transporters and Their Substrates Transporter Substrates Amino acid transporters baclofen, cyclosporin, L-dopa, gabapentin, methyldopa Peptide transporters  -lactam antibiotics, ACE inhibitors, (hPEPT1, HPT1) cephalexin, cyclosporin, methyldopa Nucleoside transporters zidovudine, zalcitabine, dipyridamole (CNT1, CNT2) Organic anion transporters ceftriaxone, benzoic acid, methotrexate (OATP1, OATP3, OATP8) pravastatin Organic cation transporters thiamine, desipramine, quinidine, (OCT1,OCT2) midazolam, verapamil Bile acid transporters chlorambucil, thyroxine (IBAT/ISBT)
  • 21.
  • 22. Facilitated Transport of Vit. B 12 Carrier B12 IF B12-IF Transported Vit. B12
  • 23.
  • 24.
  • 25.
  • 26.
  • 27.
  • 28. Receptor-mediated endocytosis Cell membrane Free drug Released drug
  • 29.
  • 30.
  • 31.
  • 32.
  • 33. Consequence of the Efflux Transporter P-glycoprotein 1) Limited drug absorption enterocyte pgp Gut lumen 2) Enhanced drug elimination Proximal tubule cells Tubule lumen hepatocytes bile 3) Limited distribution Endothelial cells capillary Brain or testes syncytiotrophoblast Maternal blood lymphocyte Adapted from: Fromm MF. Trends in Pharmacol Sci 25:423, 2004