Studies were performed in eight healthy extensive metabolizers of mephenytoin and debrisoquine to determine the effect of fluvoxamine on the activities of S-mephenytoin 4'-hydroxylase (CYP2C19) and metoprolol alpha-hydroxylase (CYP2D6). Therapeutic dosing with fluvoxamine (100 mg day-1) for 2 weeks caused a significant increase in the 0-8 h urinary S/R ratio of mephenytoin from 0.16 to 0.55 (95% confidence interval for difference between means: 0.28-0.50; P < 0.01), accompanied by a 54% reduction in the 0-8 h urinary recovery of 4'-hydroxymephenytoin (95% confidence interval for difference between means: 3.64-16.24 mg; P < 0.05). However, this did not alter the assigned phenotype of any of the subjects based on the established antimode of 0.95 (S/R-mephenytoin ratio). Two weeks after fluvoxamine was discontinued, both metabolic indices returned to their pre-study values. By contrast, fluvoxamine had no effect on either 0-8 h urinary metoprolol/alpha-hydroxymetoprolol ratio (95% confidence interval for difference between means: -0.38-0.46; P > 0.05) or the 0-8 h urinary recovery of alpha-hydroxymetoprolol (95% confidence interval for difference between means: -0.61-0.70 mg; P > 0.05). These results indicated fluvoxamine has a modest inhibitory effect on the activity of CYP2C19, but no effect on that of CYP2D6 in vivo.