Biliary excretion of flavopiridol and its glucuronides in the isolated perfused rat liver: role of multidrug resistance protein 2 (Mrp2).
Flavopiridol (FLAP) is a novel anticancer agent that is extensively glucuronidated in patients. Biliary excretion is the main elimination pathway of FLAP conjugates responsible for enterohepatic recirculation and for the main side effect diarrhea. To investigate the hepatic transport system for FLAP glucuronides, livers of Wistar and Mrp2-deficient TR- rats were perfused with FLAP (30 microM) in a single pass system. Biliary excretion and efflux into perfusate during a 60 min period greatly differ in TR- rats. While cumulative biliary excretion of M1 and M2 was significantly reduced to 4.3% and 5.4% efflux into perfusate was increased by 1.5 and 4.2-fold. This indicates that in control rats, M1 and M2 are almost exclusively eliminated into bile by Mrp2. Cumulative FLAP secretion into bile and perfusate, however, was non-significantly reduced by 36.7% and 43.2% in the mutant rat strain, suggesting that besides Mrp2, other transporters might also be involved in FLAP elimination. FLAP stimulates bile flow up to 24% in control rats, but secretion is nearly absent in TR- rats further supporting an efficient transport of FLAP glucuronides by Mrp2. FLAP (30 microM) also reversibly inhibited the Mrp2-mediated biliary elimination of bilirubin and bromsulphthalein in Wistar rats by 54% and 51%, respectively, indicating a competition with the elimination of Mrp2-specific substrates. In summary, we found that FLAP glucuronides are substrates of Mrp2 effectively inhibiting the biliary excretion of bilirubin. This may explain the increased serum bilirubin levels observed in cancer patients during FLAP therapy.
D018528:ATP-Binding Cassette Transporters; D000465:Algorithms; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D001711:Biotransformation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000493:pharmacokinetics / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation; D008297:Male; D009929:Organ Size / Q000502:physiology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013448:Sulfobromophthalein / Q000378:metabolism; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005419:Flavonoids; D020719:Glucuronides; D010880:Piperidines; D013448:Sulfobromophthalein; C077990:alvocidib