title: P-glycoprotein, multidrug-resistance associated protein 2, Cyp3a, and carboxylesterase affect the oral availability and metabolism of vinorelbine.
abstract: We investigated the interactions of the anticancer drug vinorelbine with drug efflux transporters and cytochrome P450 3A drug-metabolizing enzymes. Vinorelbine was transported by human multidrug-resistance associated protein (MRP) 2, and Mrp2 knockout mice displayed increased vinorelbine plasma exposure after oral administration, suggesting that Mrp2 limits the intestinal uptake of vinorelbine. Using P-glycoprotein (P-gp), Cyp3a-, and P-gp/Cyp3a knockout mice, we found that the absence of P-gp or Cyp3a resulted in increased vinorelbine plasma exposure, both after oral and intravenous administration. Surprisingly, P-gp/Cyp3a knockout mice displayed markedly lower vinorelbine plasma concentrations than wild-type mice upon intravenous administration but higher concentrations upon oral administration. This could be explained by highly increased formation of 4'-O-deacetylvinorelbine, an active vinorelbine metabolite, especially in P-gp/Cyp3a knockout plasma. Using wild-type and Cyp3a knockout liver microsomes, we found that 4'-O-deacetylvinorelbine formation was 4-fold increased in Cyp3a knockout liver and was not mediated by Cyp3a or other cytochrome P450 enzymes. In vitro incubation of vinorelbine with plasma revealed that vinorelbine deacetylation in Cyp3a and especially in P-gp/Cyp3a knockout mice but not in P-gp-deficient mice was strongly up-regulated. Metabolite formation in microsomes and plasma could be completely inhibited with the nonspecific carboxylesterase (CES) inhibitor bis(4-nitrophenyl) phosphate and partly with the CES2-specific inhibitor loperamide, indicating that carboxylesterase Ces2a, which was appropriately up-regulated in Cyp3a and especially in P-gp/Cyp3a knockout liver was responsible for the 4'O-deacetylvinorelbine formation. Such compensatory up-regulation can complicate the interpretation of knockout mouse data. Nonetheless, P-gp, Mrp2, Cyp3a, and Ces2a clearly restricted vinorelbine availability in mice. Variation in activity of their human homologs may also affect vinorelbine pharmacokinetics in patients.
authors: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. jurjen.lagas@slz.nl
authors: Jurjen S
authors: JS
authors: Lagas
authors: Carola W N
authors: CW
authors: Damen
authors: Robert A B
authors: RA
authors: van Waterschoot
authors: Dilek
authors: D
authors: Iusuf
authors: Jos H
authors: JH
authors: Beijnen
authors: Alfred H
authors: AH
authors: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008139:Loperamide / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D009596:Nitrophenols / Q000494:pharmacology; D015854:Up-Regulation; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000077235:Vinorelbine; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D043182:Carboxylesterase; D051544:Cytochrome P-450 CYP3A; D008139:Loperamide; D000089762:Multidrug Resistance-Associated Protein 2; D009596:Nitrophenols; D014747:Vinblastine; D000077235:Vinorelbine; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C520600:4-O-deacetyl vinorelbine; C000715087:ABCC2 protein, human; C002887:bis(4-nitrophenyl)phosphate; C095122:multidrug resistance protein 3