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K_IIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION

Department of Medicinal Chemistry (J.M.N., K.L.K., R.H.L., W.F.T.), School of Pharmacy, University of Washington, Seattle, Washington and Department of Medicine (R.A.O.), Santa Clara Valley Medical Center, San Jose, California

The goal of the study was to test the assumption that a competitive inhibition constant determined in vivo, K_iiv, like its corresponding in vitro counterpart, K_i, is independent of inhibitor concentration. Inhibition of the CYP2C9-dependent formation of (S)-7-hydroxywarfarin 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-hydroxywarfarin was inhibited by 31, 55, and 77% at the 100, 200, and 300 mg daily doses of fluconazole, respectively. K_iiv, 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 µM, respectively. These results confirm the hypothesis that K_iiv is independent of inhibitor concentration.

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