In vivo inhibition of CYP2C19 but not CYP2D6 by fluvoxamine

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.