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 the intestinal wall. We have now investigated their role in the biliary and intestinal secretion of the anticancer drugs doxorubicin (unlabeled: 5 mg/kg) and vinblastine ((3)H-labeled: 1 mg/kg) i.v. administered to wild-type and mdr1a P-glycoprotein knockout [mdr1a(-/-)] mice. At 90 min after drug administration, levels of unchanged drug and metabolites in plasma, intestinal contents, and bile were determined by high-performance liquid chromatography and radioactivity by liquid scintillation counting. The bile of both wild-type and mdr1a(-/-) mice contained only minor amounts of unchanged vinblastine, whereas the total biliary secretion of unknown (3)H-labeled breakdown products was about 25 to 30% of the dose. The direct secretion of unchanged vinblastine through the gut wall was 6.7 and 3.3% of the dose in wild-type and mdr1a(-/-) mice, respectively. The biliary secretion of unchanged doxorubicin decreased from 13.3% of the dose to only 2.4% in the absence of mdr1a 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 affects the fate of doxorubicin chiefly by diminishing secretion of parent drug into bile.
van Asperen
J
J
Department of Clinical Chemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands.
van Tellingen
O
O
Beijnen
J H
JH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009279:Naphthacenes / Q000097:blood / Q000378:metabolism; D014747:Vinblastine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009279:Naphthacenes; C074869:7-deoxy-13-dihydroadriamycinone; D014747:Vinblastine; D004317:Doxorubicin; C049326:7-deoxyadriamycin aglycone