title: Kiiv, an in vivo parameter for predicting the magnitude of a drug interaction arising from competitive enzyme inhibition.
abstract: The goal of the study was to test the assumption that a competitive inhibition constant determined in vivo, Kiiv, like its corresponding in vitro counterpart, Ki, is independent of inhibitor concentration. Inhibition of the CYP2C9-dependent formation of (S)-7-hydroxy-warfarin from (S)-warfarin was measured in seven healthy subjects at three different doses of fluconazole. Prothrombin time measurements showed increasing anticoagulant activity with increasing fluconazole dose. The pharmacokinetic parameters calculated from the (S)- and (R)-warfarin plasma levels were consistent with previous studies. Fluconazole reduced the clearance of (S)-warfarin to a greater extent than that of (R)-warfarin. The decrease in clearance of both warfarin enantiomers was fluconazole dose-dependent. The formation of (S)-7-hydroxy-warfarin was inhibited by 31, 55, and 77% at the 100, 200, and 300 mg daily doses of fluconazole, respectively. Kiiv, values calculated from these data based on plasma fluconazole levels at each dose and data from earlier work at 400-mg daily doses of fluconazole were 30.7 +/- 23.7, 19.6 +/- 3.8, 17.9 +/- 7.5, and 19.8 +/- 3.5 microM, respectively. These results confirm the hypothesis that Kiiv is independent of inhibitor concentration.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Neal
authors.forename: Kent L
authors.initials: KL
authors.lastname: Kunze
authors.forename: René H
authors.initials: RH
authors.lastname: Levy
authors.forename: Robert A
authors.initials: RA
authors.lastname: O'Reilly
authors.forename: William F
authors.initials: WF
authors.lastname: Trager
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects*; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004791:Enzyme Inhibitors; D015725:Fluconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D011517:Prothrombin Time; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014859:Warfarin; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases