Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo

Objective: In vitro studies have shown that tacrine is metabolized by cytoc hrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incrimi nated with tacrine-induced hepatotoxicity. The aim of this study was to est ablish whether the potent CYP1A2 inhibitor fluvoxamine in clinically releva nt doses could inhibit tacrine metabolism. Methods: Eighteen healthy young men were enrolled in an open, randomized cr ossover study. In the first study period a single oral dose of tacrine 40 m g was given. In the second period the volunteers were randomized to mainten ance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of t acrine 20 mg was given. Results: Fluvoxamine was found to be a very potent inhibitor of tacrine met abolism. A fractional decrement in tacrine clearance of approximately 85% w as found with both fluvoxamine doses, which was in good agreement with a pr ediction based on in vitro data. The medians of the steady-state concentrat ion of fluvoxamine were 43 nM (range 25-49) and 70 nM (range 44-124) in the 50 mg per day and 100 mg per day groups, respectively. The steady-state co ncentration of fluvoxamine correlated with the fractional decrement in tacr ine clearance (Spearman R-s = 0.53, P < 0.05). Modest, but statistically si gnificant, reductions in the formation of the metabolites 1- and 2-hydroxyt acrine were found during concomitant fluvoxamine treatment. Conclusion: Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical rel evance. Whether concomitant fluvoxamine treatment reduces tacrine-induced h epatotoxicity needs further study.