| Title : Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo - Larsen_1999_Eur.J.Clin.Pharmacol_55_375 |
| Author(s) : Larsen JT , Hansen LL , Spigset O , Brosen K |
| Ref : European Journal of Clinical Pharmacology , 55 :375 , 1999 |
| Abstract : 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. CONCLUSION: 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. |
| ESTHER : Larsen_1999_Eur.J.Clin.Pharmacol_55_375 |
| PubMedSearch : Larsen_1999_Eur.J.Clin.Pharmacol_55_375 |
| PubMedID: 10456487 |
Larsen JT, Hansen LL, Spigset O, Brosen K (1999)
Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo
European Journal of Clinical Pharmacology
55 :375
Larsen JT, Hansen LL, Spigset O, Brosen K (1999)
European Journal of Clinical Pharmacology
55 :375