Author(s): Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW,
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Abstract In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(-/-) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(-/-) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(-/-) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11\% in wt mice to 35\% in mdr1a(-/-) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40\% (after i.v. administration) and 87\% (after oral administration) of the administered dose in wt mice to below 3\% in mdr1a(-/-) mice. Biliary excretion was not significantly different in wt and mdr1a(-/-) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11\% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3\% in mdr1a(-/-) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.
This article was published in Proc Natl Acad Sci U S A
and referenced in Clinical Pharmacology & Biopharmaceutics