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P-gp, Mrp2, Cyp3a, and Carboxylesterase Affect the Oral Availability and Metabolism of Vinorelbine.

Mol Pharmacol. 2012 Jul 5;

Authors: Lagas JS, Damen CW, van Waterschoot RA, Iusuf D, Beijnen JH, Schinkel AH


We investigated the interactions of the anticancer drug vinorelbine with drug-efflux transporters and Cytochrome P450 3A (CYP3A) drug-metabolizing enzymes. Vinorelbine was transported by human MRP2, and Mrp2 knockout mice displayed increased vinorelbine plasma exposure after oral administration, suggesting that Mrp2 limits the intestinal uptake of vinorelbine. Using P-gp-, Cyp3a-, and P-gp/Cyp3a knockout mice, we found that absence of P-gp or Cyp3a resulted in increased vinorelbine plasma exposure, both after oral and i.v. administration. Surprisingly, P-gp/Cyp3a knockout mice displayed markedly lower vinorelbine plasma concentrations than wild-type mice upon i.v. 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 not mediated by Cyp3a or other P450 enzymes. In vitro incubation of vinorelbine with plasma revealed that vinorelbine deacetylation in Cyp3a- and especially P-gp/Cyp3a knockout mice, but not P-gp-deficient mice, was strongly upregulated. Metabolite formation in microsomes and plasma could be completely inhibited with the non-specific carboxylesterase inhibitor bis(4-nitrophenyl) phosphate and partly with the CES2-specific inhibitor loperamide, indicating that carboxylesterase Ces2a, which was appropriately upregulated in Cyp3a- and especially P-gp/Cyp3a knockout liver, was responsible for the 4'O-deacetylvinorelbine formation. Such compensatory upregulation 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 homologues may affect vinorelbine pharmacokinetics in patients as well.

PMID: 22767610 [PubMed - as supplied by publisher]