Lagas_2012_Mol.Pharmacol_82_636

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.