Fluvoxamine is a Potent Inhibitor of the Metabolism of Caffeinein vitro

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Abstract
The selective serotonin re‐uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYP1A2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYP1A2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been describedin vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interactionin vitroin human liver microsomes. A high‐performance liquid chromatography method was developed in order to assay 1, 3‐dimethylxanthine, 1, 7‐dimethylxanthine, 3, 7‐dimethylxanthine and 1, 3, 7‐trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol · mg protein−1· hr−1. As expected, fluvoxamine was a very potent inhibitor of the formation of theN‐demethylated caffeine metabolites, displaying Kivalues of 0.08–0.28 μM. The formation of 1, 7‐dimethylxanthine was virtually abolished by 10 μM of fluvoxamine, indicating that theN3‐demethylation of caffeine is almost exclusively catalysed by CYP1A2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1, 3, 7‐trimethyluric acid formation with K s of 0.75 μM and 5 μM, respectively, thus further supporting the involvement of CYP3A4 in the 8‐hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeinein vitro.

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