Received for publication February 28, 2006.
Revised May 2, 2006.
Accepted for publication May 3, 2006.

Selective metabolism of vincristine in vitro by CYP3A5

Abstract

Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in CYP expression may contribute to the interindividual variability in clinical response, but the contributions of individual CYPs and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed CYPs, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only CYPs to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycantharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared to CYP3A4 (9 to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of co-expressed cytochrome b₅, but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.

Key words: anticancer agents, clinical pharmacology, CYP3A, cytochrome P450, enzyme kinetics, ethnic differences, kinetic modeling, mass spectrometry, pharmacogenetics, structure elucidation

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