1 PASSAGE OF XENOBIOTICS PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL ACROSS BIOLOGICAL MEMBRANES MEMBRANES I. I. PHYSICOCHEMICAL PHYSICOCHEMICAL DETERMINANTS OF THE PASSAGE OF DETERMINANTS OF THE PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL XENOBIOTICS ACROSS BIOLOGICAL MEMBRANES MEMBRANES
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1 PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL MEMBRANES I.PHYSICOCHEMICAL DETERMINANTS OF THE PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL MEMBRANES.
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PASSAGE OF PASSAGE OF XENOBIOTICS ACROSS XENOBIOTICS ACROSS
BIOLOGICAL BIOLOGICAL MEMBRANESMEMBRANES
I.I. PHYSICOCHEMICAL PHYSICOCHEMICAL DETERMINANTS OF THE DETERMINANTS OF THE PASSAGE OF XENOBIOTICS PASSAGE OF XENOBIOTICS ACROSS BIOLOGICAL ACROSS BIOLOGICAL MEMBRANESMEMBRANES
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A. Membrane CharacteristicsA. Membrane Characteristics
•solubility in unstirred layer around cellsolubility in unstirred layer around cell
cell
unstirredlayer
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II. II. MECHANISMS OF BIOTRANSPORTMECHANISMS OF BIOTRANSPORTBiotransportBiotransport
The translocation of a solute from one The translocation of a solute from one side of a biological barrier to the other side of a biological barrier to the other side in the intact form.side in the intact form.
A. Passive DiffusionA. Passive Diffusion
semi-permeable membrane
External Internal
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Fick’s Law of DiffusionFick’s Law of Diffusion
21 CCh
DAK
dt
dQ p
dQ/dt - rate of diffusion D - diffusion coefficient
A - surface area of membrane Kp - partition coefficienth - membrane thickness
C1 - C2 = concentration difference for solute
Generally, C1>>C2
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ABSORPTION FROM RAT ABSORPTION FROM RAT STOMACH STOMACH AND SMALL AND SMALL
INTESTINEINTESTINE % absorbed in 1 hr % absorbed in 10 min
P-glycoprotein: P-glycoprotein: MDR1 (ABCB1)MDR1 (ABCB1)Multidrug Resistance Protein: Multidrug Resistance Protein: MRP1 MRP1 (ABCC1)(ABCC1)Breast Cancer Resistance Protein: Breast Cancer Resistance Protein: BCRP BCRP (ABCG2)(ABCG2)
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Plasma levels of saquinavir versus time after oral administration in Plasma levels of saquinavir versus time after oral administration in wild type (open circles) and Mdr1awild type (open circles) and Mdr1a-/--/-/1b/1b-/--/- mice. mice. From: Huisman MT, et al. P-From: Huisman MT, et al. P-glycoprotein limits oral availability, brain and fetal penetration of saquinavir even with glycoprotein limits oral availability, brain and fetal penetration of saquinavir even with high doses of ritonavir. high doses of ritonavir. Mol PharmacolMol Pharmacol 59:806-813, 2001 59:806-813, 2001
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Consequence of the Efflux Transporter P-glycoproteinConsequence of the Efflux Transporter P-glycoprotein
1) Limited drug absorption
enterocytepgp
Gut lumen
2) Enhanced drug elimination2) Enhanced drug eliminationProximal tubule cells
Tubule lumen
hepatocytes
bile3) Limited distribution
Endothelial cells
capillary
Brain or testessyncytiotrophoblast
Maternal blood
lymphocyte
Adapted from: Fromm MF. Trends in Pharmacol Sci 25:423, 2004
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.