The role of MDR1A P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice

Drug-transporting P-glycoproteins are abundantly present in the liver and t he intestinal wall. We have now investigated their role in the biliary and intestinal secretion of the anticancer drugs doxorubicin (unlabeled: 5 mg/k g) and vinblastine (H-3-labeled: 1 mg/kg) i.v. administered to wild-type an d mdr1a P-glycoprotein knockout [mdr1a(-/-)] mice. At 90 min after drug adm inistration, levels of unchanged drug and metabolites in plasma, intestinal contents, and bile were determined by high-performance liquid chromatograp hy and radioactivity by liquid scintillation counting. The bile of both wil d-type and mdr1a(-/-) mice contained only minor amounts of unchanged vinbla stine, whereas the total biliary secretion of unknown H-3-labeled breakdown products was about 25 to 30% of the dose. The direct secretion of unchange d vinblastine through the gut wall was 6.7 and 3.3% of the dose in wild-typ e and mdr1a(-/-) mice, respectively. The biliary secretion of unchanged dox orubicin decreased from 13.3% of the dose to only 2.4% in the absence of md r1a P-glycoprotein. Approximately 10% of the dose was secreted as unchanged doxorubicin into the intestinal contents of both types of mice. Thus, the absence of mdr1a P-glycoprotein affects the fate of vinblastine chiefly by diminishing secretion into the lumen of the small intestine, whereas it aff ects the fate of doxorubicin chiefly by diminishing secretion of parent dru g into bile.