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 tolbutamide orally. In period B, the volunteers were randomly assigned to one of two groups. Each group took either 150 mg or 75 mg of fluvoxamine a day 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 analyzed for tolbutamide and its two metabolites, 4-hydroxytolbutamide and carboxytolbutamide by means of HPLC.


RESULTS
During treatment with fluvoxamine, there was a statistically significant decrease in the median of the total clearance of tolbutamide, from 845 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 that received 150 mg/d of tolbutamide. The clearance by means of 4-hydroxytolbutamide and carboxytolbutamide was significantly reduced in both groups (ie, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutamide per day and from 723 mL/h to 457 mL/h in the group that received 75 mg of tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4-hydroxylation during treatment with 150 mg/d of fluvoxamine compared with 75 mg/d, but the difference was not statistically significant.


CONCLUSIONS
Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.
Madsen
H
H
Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense University.
Enggaard
T P
TP
Hansen
L L
LL
Klitgaard
N A
NA
Brøsen
K
K
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000187:drug effects; D002384:Catalysis; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D016666:Fluvoxamine; D007004:Hypoglycemic Agents; D017367:Selective Serotonin Reuptake Inhibitors; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases; D014044:Tolbutamide; C450260:CYP2C9 protein, human