Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo.
OBJECTIVE
In vitro studies have shown that tacrine is metabolized by cytochrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incriminated with tacrine-induced hepatotoxicity. The aim of this study was to establish whether the potent CYP1A2 inhibitor fluvoxamine in clinically relevant doses could inhibit tacrine metabolism.


METHODS
Eighteen healthy young men were enrolled in an open, randomized crossover study. In the first study period a single oral dose of tacrine 40 mg was given. In the second period the volunteers were randomized to maintenance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of tacrine 20 mg was given.


RESULTS
Fluvoxamine was found to be a very potent inhibitor of tacrine metabolism. A fractional decrement in tacrine clearance of approximately 85% was found with both fluvoxamine doses, which was in good agreement with a prediction based on in vitro data. The medians of the steady-state concentration 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 concentration of fluvoxamine correlated with the fractional decrement in tacrine clearance (Spearman Rs = 0.53, P < 0.05). Modest, but statistically significant, reductions in the formation of the metabolites 1- and 2-hydroxytacrine were found during concomitant fluvoxamine treatment.


CONCLUSIONS
Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical relevance. Whether concomitant fluvoxamine treatment reduces tacrine-induced hepatotoxicity needs further study.
Larsen
J T
JT
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense. teilmann@dadlnet.dk
Hansen
L L
LL
Spigset
O
O
Brøsen
K
K
D000328:Adult; D002800:Cholinesterase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000502:physiology*; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013619:Tacrine / Q000097:blood / Q000493:pharmacokinetics*
D002800:Cholinesterase Inhibitors; D019388:Cytochrome P-450 CYP1A2; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors; D013619:Tacrine