OBJECTIVE: Tacrine is extensively metabolized by cytochrome P4501A2 (CYP1A2). 
Fluvoxamine, a potent CYP1A2 inhibitor, may be coadministered with tacrine. The 
aim of this study was to examine the influence of fluvoxamine administration on 
the disposition kinetics of single-dose tacrine administration.
METHODS: Thirteen healthy volunteers participated in this double-blind, 
randomized crossover study, which compared the effects of fluvoxamine (100 
mg/day during 6 days) and placebo on the pharmacokinetics of a single oral dose 
of tacrine (40 mg).
RESULTS: Fluvoxamine caused a significant increase in tacrine area under the 
plasma concentration versus time curve (AUC): arythmetic mean, 27 (95% 
confidence interval [CI], 19 to 38) ng.hr/ml versus 224 (95% CI, 166 to 302) ng. 
hr/ml. Fluvoxamine caused a decrease in the apparent oral clearance of tacrine 
from 1683 +/- 802 to 200 +/- 106 L/hr (mean +/- SD), which was explained by a 
decrease in its nonrenal clearance. Five subjects had gastrointestinal side 
effects during fluvoxamine administration. Fluvoxamine administration was 
associated with significant increases in the plasma AUC values of three 
monohydroxylated tacrine metabolites and in the total urinary recovery 
measurements of tacrine and its metabolites (9.1% +/- 4.6% versus 24.0% +/- 2.6% 
of recovery). These results may be attributable to fluvoxamine-dependent 
inhibition of CYP1A/, which is responsible of the biotransformation of tacrine 
into its monohydroxylated metabolites and further into dihydroxylated and 
reactive metabolites.
CONCLUSION: Fluvoxamine inhibits the metabolism of tacrine. CYP1A2 may be the 
target of this inhibition. Fluvoxamine may modulate the hepatotoxicity of 
tacrine, depending on the relative contribution of tacrine and its reactive 
metabolites to this toxicity.