PT  - JOURNAL ARTICLE
AU  - John M. Neal
AU  - Kent L. Kunze
AU  - René H. Levy
AU  - Robert A. O'Reilly
AU  - William F. Trager
TI  - <em>K</em><sub>I</sub>IV, AN IN VIVO PARAMETER FOR PREDICTING THE
 MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME
 INHIBITION
AID  - 10.1124/dmd.31.8.1043
DP  - 2003 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1043--1048
VI  - 31
IP  - 8
4099  - http://dmd.aspetjournals.org/content/31/8/1043.short
4100  - http://dmd.aspetjournals.org/content/31/8/1043.full
SO  - Drug Metab Dispos2003 Aug 01; 31
AB  - 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-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. 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 μM, respectively. These results confirm the hypothesis that Kiiv is independent of inhibitor concentration. The American Society for Pharmacology and Experimental Therapeutics