title: Quantitative correlations among CYP3A sensitive substrates and inhibitors: literature analysis.
abstract: As a follow-up to the new classification of CYP3A inhibitors, the present work was undertaken to search for quantitative correlations of AUC ratios between sensitive substrates and midazolam (reference). A large set of clinical studies was obtained utilizing the M&T Drug Interaction Database, and recent Product Labels. Linear relationships were found between midazolam and four CYP3A substrates: simvastatin, buspirone, triazolam and eplerenone. Simvastatin and buspirone were consistently more sensitive than midazolam, independent of the inhibitor. Quantitative correlations of AUC ratios between four CYP3A inhibitors (fluconazole, erythromycin, verapamil, diltiazem) and ketoconazole (400 mg/day) were also uncovered. The average potencies of these inhibitors relative to ketoconazole were 27% for erythromycin, 17% for fluconazole and 19% for verapamil.
authors.affiliation: Drug Interaction Database Unit, University of Washington, Department of Pharmaceutics, Seattle, WA 98195, USA. imaj@u.washington.edu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ragueneau-Majlessi
authors.forename: Xavier
authors.initials: X
authors.lastname: Boulenc
authors.forename: Clemence
authors.initials: C
authors.lastname: Rauch
authors.forename: Houda
authors.initials: H
authors.lastname: Hachad
authors.forename: René H
authors.initials: RH
authors.lastname: Levy
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D016208:Databases, Factual; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000145:classification / Q000493:pharmacokinetics; D004917:Erythromycin / Q000493:pharmacokinetics; D015725:Fluconazole / Q000494:pharmacology; D007654:Ketoconazole / Q000493:pharmacokinetics; D008874:Midazolam / Q000493:pharmacokinetics / Q000592:standards; D013379:Substrate Specificity; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D004917:Erythromycin; D015725:Fluconazole; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole