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Research ArticleArticle

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 and Jamie L. Renbarger
Drug Metabolism and Disposition September 2013, 41 (9) 1651-1661; DOI: https://doi.org/10.1124/dmd.113.051094
Ariel R. Topletz
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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Jennifer B. Dennison
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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Robert J. Barbuch
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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Chad E. Hadden
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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Stephen D. Hall
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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Jamie L. Renbarger
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine (A.R.T., J.B.D., S.D.H., J.L.R.); and Lilly Research Laboratories, Eli Lilly and Company (R.J.B., C.E.H., S.D.H.), Indianapolis, Indiana
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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.

Footnotes

    • Received January 11, 2013.
    • Accepted June 17, 2013.
  • This work was supported by the National Institutes of Health National Center for Research Resources [K23 RR019956].

  • dx.doi.org/10.1124/dmd.113.051094.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (9)
Drug Metabolism and Disposition
Vol. 41, Issue 9
1 Sep 2013
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Research ArticleArticle

Vinorelbine Metabolism by CYP3A

Ariel R. Topletz, Jennifer B. Dennison, Robert J. Barbuch, Chad E. Hadden, Stephen D. Hall and Jamie L. Renbarger
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1651-1661; DOI: https://doi.org/10.1124/dmd.113.051094

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Research ArticleArticle

Vinorelbine Metabolism by CYP3A

Ariel R. Topletz, Jennifer B. Dennison, Robert J. Barbuch, Chad E. Hadden, Stephen D. Hall and Jamie L. Renbarger
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1651-1661; DOI: https://doi.org/10.1124/dmd.113.051094
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