Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide

Objective: Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9, Methods: The study was carried out as an open, randomized, crossover design with 14 healthy participants. In period A, all volunteers took 500 mg of t olbutamide orally, In period B, the volunteers were randomly assigned to on e of two groups, Each group took either 150 mg or 75 mg of fluvoxamine a da y for 5 days (day -3 to day 2), The groups then took 500 mg of tolbutamide as a single dose (day 0), In both periods, blood and urine were sampled at regular intervals. Plasma was analyzed for tolbutamide, and urine was analy zed for tolbutamide and its two metabolites, 4-hydroxytolbutamide and carbo xytolbutamide by means of HPLC. Results: During treatment with fluvoxamine, there was a statistically signi ficant decrease in the median of the total clearance of tolbutamide, from 8 45 mL/h to 688 mL/h, among the volunteers who received 75 mg/d, There was a reduction that reached borderline statistical significance in the group th at received 150 mg/d of tolbutamide. The clearance by means of 4-hydroxytol butamide and carboxytolbutamide was significantly reduced in both groups (i e, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutami de per day and from 723 mL/h to 457 mL/h in the group that received 75 mg o f tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4-hydroxylation during treatment with 150 mg/d of fluvoxa mine compared with 75 mg/d, but the difference was not statistically signif icant, Conclusion: Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.