Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites

Ying Hong Wang, David R. Jones, Stephen D. Hall

Research output: Contribution to journalArticle

180 Citations (Scopus)

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-desalkyl-verapamil (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.

Original languageEnglish
Pages (from-to)259-266
Number of pages8
JournalDrug Metabolism and Disposition
Volume32
Issue number2
DOIs
StatePublished - Feb 2004

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Cytochrome P-450 CYP3A
Enantiomers
Metabolites
Verapamil
Drug interactions
Drug Interactions
Area Under Curve
Complementary DNA
Pharmacokinetics
Spectrophotometry
Midazolam
Liver Microsomes
Substrates
Kinetic parameters
Metabolism
Pharmaceutical Preparations
Liver
Oral Administration
norverapamil

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. / Wang, Ying Hong; Jones, David R.; Hall, Stephen D.

In: Drug Metabolism and Disposition, Vol. 32, No. 2, 02.2004, p. 259-266.

Research output: Contribution to journalArticle

Wang, Ying Hong ; Jones, David R. ; Hall, Stephen D. / Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. In: Drug Metabolism and Disposition. 2004 ; Vol. 32, No. 2. pp. 259-266.
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