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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2004-1-27
pubmed:abstractText
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 microM for R-verapamil, 0.64 min(-1) and 2.97 microM for S-verapamil, 1.12 min(-1) and 5.89 microM for (+/-)-norverapamil, and 0.07 min(-1) and 7.93 microM 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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
32
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
259-66
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites.
pubmed:affiliation
Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA. yiwang@iupui.edu
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, U.S. Gov't, P.H.S.