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Research ArticleArticle

PREDICTION OF CYTOCHROME P450 3A INHIBITION BY VERAPAMIL ENANTIOMERS AND THEIR METABOLITES

Ying-Hong Wang, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition February 2004, 32 (2) 259-266; DOI: https://doi.org/10.1124/dmd.32.2.259
Ying-Hong Wang
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Stephen D. Hall
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Abstract

Verapamil inhibition of CYP3A activity results in many drug-drug interactions with CYP3A substrates, but the mechanism of inhibition is unclear. The present study showed that verapamil enantiomers and their major metabolites [norverapamil and N-desalkylverapamil (D617)] inhibited CYP3A in a time- and concentration-dependent manner by using pooled human liver microsomes and the cDNA-expressed CYP3A4 (+b5). The values of the inactivation kinetic parameters kinact and KI obtained with the cDNA-expressed CYP3A4 (+b5) were 0.39 min-1 and 6.46 μM for R-verapamil, 0.64 min-1 and 2.97 μM for S-verapamil, 1.12 min-1 and 5.89 μM for (±)-norverapamil, and 0.07 min-1 and 7.93 μM for D617. Based on the ratio of kinact and KI, the inactivation potency of verapamil enantiomers and their metabolites was in the following order: S-norverapamil > S-verapamil > R-norverapamil > R-verapamil > D617. Using dual beam spectrophotometry, we confirmed that metabolic intermediate complex formation with CYP3A was the mechanism of inactivation for all compounds. The in vitro unbound fraction was 0.84 for S-verapamil, 0.68 for R-verapamil, and 0.84 for (±)-norverapamil. A mechanism-based pharmacokinetic model predicted that the oral area under the curve (AUC) of a CYP3A substrate that is eliminated completely (fm = 1) by the hepatic CYP3A increased 1.6- to 2.2-fold after repeated oral administration of verapamil. For midazolam (fm = 0.9), a drug that undergoes extensive intestinal wall metabolism, the predicted increase in oral AUC was 3.2- to 4.5-fold. The predicted results correlate well with the in vivo drug interaction data, suggesting that the model is suitable for predicting drug interactions by mechanism-based inhibitors.

Footnotes

  • ↵1 Abbreviations used are: D617, N-desalkylverapamil; AUC, area under the concentration-time curve; MIC, metabolic intermediate complex; P450, cytochrome P450; HPLC, high-performance liquid chromatography; HLMs, human liver microsome; P-gp, P-glycoprotein; FG, intestinal wall bioavailability.

  • This research is supported by National Institutes of Health Grant GM67308.

    • Received June 26, 2003.
    • Accepted October 7, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (2)
Drug Metabolism and Disposition
Vol. 32, Issue 2
1 Feb 2004
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Research ArticleArticle

PREDICTION OF CYTOCHROME P450 3A INHIBITION BY VERAPAMIL ENANTIOMERS AND THEIR METABOLITES

Ying-Hong Wang, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition February 1, 2004, 32 (2) 259-266; DOI: https://doi.org/10.1124/dmd.32.2.259

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Research ArticleArticle

PREDICTION OF CYTOCHROME P450 3A INHIBITION BY VERAPAMIL ENANTIOMERS AND THEIR METABOLITES

Ying-Hong Wang, David R. Jones and Stephen D. Hall
Drug Metabolism and Disposition February 1, 2004, 32 (2) 259-266; DOI: https://doi.org/10.1124/dmd.32.2.259
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