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-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.
Footnotes
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↵1 Abbreviations used are: P450, cytochrome P450; Kiiv, in vivo constant for competitive inhibition of an enzyme; Ki, in vitro constant for competitive inhibition of an enzyme; AUC, area under the curve; PT, the response of the prothrombin time; CL, clearance limits; F, bioavailability; Vss, apparent volume of distribution.
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↵2 The classic expression for competitive enzyme inhibition is
where i = fraction of inhibition, [I] = inhibitor
concentration, [S] = substrate concentration, Km
is the Michaelis-Menten constant for the substrate, and Ki
is the inhibition constant. -
↵3 The difference between the mean fluconazole concentration over 24 h and the 24-h fluconazole concentration, ranges between 10 and 20% with the mean value being higher (Kunze and Trager, 1996). Thus, use of the 24-h value in eq. 2 would be expected to lead to a slightly lower value for Kiiv than would be obtained using the mean value. This is exactly what is found. Using the data from the earlier paper by Kunze and Trager (1996), the mean fluconazole concentrations over 24 h yielded a Kiiv of 22.5 ± 3.5 μM whereas the fluconazole concentrations from the same study at 24-h postdose yielded a Kiiv of 19.8 ± 3.5 μM.
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This study was supported in part by Grant 32165 from the National Institutes of Health (Bethesda, MD).
- Received January 7, 2003.
- Accepted April 22, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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