Source:http://linkedlifedata.com/resource/pubmed/id/14744949
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
2004-1-27
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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.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channel Blockers,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/Verapamil,
http://linkedlifedata.com/resource/pubmed/chemical/norverapamil
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0090-9556
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
32
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
259-66
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:14744949-Administration, Oral,
pubmed-meshheading:14744949-Area Under Curve,
pubmed-meshheading:14744949-Calcium Channel Blockers,
pubmed-meshheading:14744949-Chromatography, High Pressure Liquid,
pubmed-meshheading:14744949-Cytochrome P-450 CYP3A,
pubmed-meshheading:14744949-Cytochrome P-450 Enzyme System,
pubmed-meshheading:14744949-Drug Interactions,
pubmed-meshheading:14744949-Humans,
pubmed-meshheading:14744949-Microsomes, Liver,
pubmed-meshheading:14744949-Models, Biological,
pubmed-meshheading:14744949-Stereoisomerism,
pubmed-meshheading:14744949-Verapamil
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pubmed:year |
2004
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pubmed:articleTitle |
Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites.
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pubmed:affiliation |
Indiana University School of Medicine, Division of Clinical Pharmacology, Indianapolis, IN 46202, USA. yiwang@iupui.edu
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pubmed:publicationType |
Journal Article,
Comparative Study,
In Vitro,
Research Support, U.S. Gov't, P.H.S.
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