Abstract
A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (Ki) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe.Ki values based on total added fluvoxamine concentration (Ki,total) and unbound fluvoxamine concentration (Ki,ub) were calculated, and interindividual variability inKi values was examined in six nonfatty livers. Ki,total values varied with microsomal protein concentration, whereas the correspondingKi,ub values were within a narrow range (70–80 nM). In vivo inhibition constants (Kiiv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (r2 = 0.88,p < 0.001). The mean (±S.D.) values ofKiiv based on total and unbound plasma concentrations were 13.5 ± 5.6 and 1.9 ± 1.1 nM, respectively. Comparison of in vitro and in vivoKi values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.
Footnotes
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This work was supported by grants from the National Institutes of Health (GM-32165) and the General Clinical Research Center, University of Washington (MO1RR00037).
- Abbreviations used are::
- P450
- cytochrome P450
- 4-OH-meph
- 4-hydroxy-mephenytoin
- p-HPPH
- 5-(4′-hydroxyphenyl)-5-phenylhydantoin
- IS
- internal standard
- HLM
- human liver microsome
- LC-MSD
- liquid chromatography-mass spectrometric detection
- AUC
- area under the plasma concentration-time curve
- Received September 30, 2002.
- Accepted December 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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