General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs

Clinical Pharmacokinetics
Yoshiyuki OhnoHiroshi Suzuki


Cytochrome P450 (CYP) 3A4 is the most prevalent metabolising enzyme in the human liver and is also a target for various drug interactions of significant clinical concern. Even though there are numerous reports regarding drug interactions involving CYP3A4, it is far from easy to estimate all potential interactions, since too many drugs are metabolised by CYP3A4. For this reason, a comprehensive framework for the prediction of CYP3A4-mediated drug interactions would be of considerable clinical importance. The objective of this study was to provide a robust and practical method for the prediction of drug interactions mediated by CYP3A4 using minimal in vivo information from drug-interaction studies, which are often carried out early in the course of drug development. The analysis was based on 113 drug-interaction studies reported in 78 published articles over the period 1983-2006. The articles were used if they contained sufficient information about drug interactions. Information on drug names, doses and the magnitude of the increase in the area under the concentration-time curve (AUC) were collected. The ratio of the contribution of CYP3A4 to oral clearance (CR(CYP)(3A4)) was calculated for 14 substrates (midazolam, alprazolam, b...Continue Reading


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