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The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine.


Drug Metab Dispos. 2013 Jun 18;


Authors: Topletz AR, Dennison JB, Barbuch RJ, Hadden CE, Hall SD, Renbarger JL


Abstract

Vinorelbine is a semi-synthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human CYPs and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the CYPs capable of oxidizing vinorelbine using a panel of human enzymes and selective CYP inhibitors in HLMs. For CYP3A4 co-expressed with cytochrome b5 (CYP3A4+b5) and CYP3A5+b5, the Michaelis-Menten constants for vinorelbine were 2.6 μM and 3.6 μM, respectively, but the Vmax of 1.4 pmol/min/pmol was common to both enzymes. In HLMs the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. Using radiolabeled vinorelbine substrate there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b5 and CYP3A5+b5 as determined by NMR and MS analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism, the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

PMID: 23780963 [PubMed - as supplied by publisher]