The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine

Ariel R. Topletz, Jennifer B. Dennison, Robert J. Barbuch, Chad E. Hadden, Stephen D. Hall, Jamie Renbarger

Research output: Contribution to journalArticle

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Abstract

Vinorelbine is a semisynthetic 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 cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b5 (CYP3A4+b5) and CYP3A5 +b5, the Michaelis-Menten constants for vinorelbine were 2.6 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. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b5 and CYP3A5+b5 as determined by NMR and mass spectrometry 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.

Original languageEnglish
Pages (from-to)1651-1661
Number of pages11
JournalDrug Metabolism and Disposition
Volume41
Issue number9
DOIs
StatePublished - Sep 2013

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Cytochrome P-450 CYP3A
Liver Microsomes
Vinca Alkaloids
vinorelbine
Cytochromes b5

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine. / Topletz, Ariel R.; Dennison, Jennifer B.; Barbuch, Robert J.; Hadden, Chad E.; Hall, Stephen D.; Renbarger, Jamie.

In: Drug Metabolism and Disposition, Vol. 41, No. 9, 09.2013, p. 1651-1661.

Research output: Contribution to journalArticle

Topletz, Ariel R. ; Dennison, Jennifer B. ; Barbuch, Robert J. ; Hadden, Chad E. ; Hall, Stephen D. ; Renbarger, Jamie. / The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine. In: Drug Metabolism and Disposition. 2013 ; Vol. 41, No. 9. pp. 1651-1661.
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