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lec 5 Intestinal TransportIIsm

lec 5 Intestinal TransportIIsm - Absorption Distribution...

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1 •A bsorption •D istribution •M etabolism •E xcretion • How do the gene products of CYP3A4 and MDR1 act synergistically in the small intestine to reduce the uptake of xenobiotics? •You are designing a novel HIV drug treatment and find that uptake of this drug is much less than you expected. You believe that it is either metabolized in the small intestine by CYP3A4 or pumped out of the enterocytes by P-gp. Design an experiment to determine which mechanism is responsible for the poor absorption of your novel drug. •From your experiments you find that neither CYP3A4 or P-gp is responsible for the poor absorption of your HIV drug. What other mechanisms could be responsible? • Explain the role of MDR's, MRP's, and MXR's in intestinal xenobiotic transport. •Illustrate the mechanism of action for MDR1 and MRP1. •Explain the difference in xenobiotic absorption orally and by i.v. in MDR1 (-/-) and MDR1 (+/+) mice. Learning Objectives
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2 Readings Hiroshi Suzuki , Yuichi Sugiyama. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine European Journal of Pharmaceutical Sciences 12 (2000) 3–12 Lipophilicity Hi Lo Log P and Log D (pH 7.4) vs. F a for 86 commercial drugs Fraction Absorbed More absorption than expected? Less absorption than expected? Possible explanations? Zhu , C.et al. Eur. J. Med. Chem. 37 , pp. 399–407,2002
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3 Advanced Drug Delivery Reviews 50 (2001) S 13–S 31 Effects of active export on xenobiotic uptake Intestinal transport 3 known classes of xenobiotic transporters in Gut MDR- two members MRP - nine members MXR - two member
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