Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide

Objective: To investigate the interaction between fluvoxamine and chloroguanide (INN, proguanil) to confirm that fluvoxamine inhibits CYP2C19. Methods: The study was carried out with a randomized, in vivo, crossover design. Six volunteers were extensive metabolizers of the S-mephenytoin oxidation polymorphism, and six volunteers were poor metabolizers. In period A of the study, each subject took 200 mg chloroguanide orally. In period B, each subject took 100 mg/day fluvoxamine for 8 days and on day 6 ingested 200 mg chloroguanide. In both periods, blood and urine were sampled at regular intervals. Chloroguanide and its two metabolites cycloguanil and 4-chlorphenylbiguanide in plasma and in urine were assayed by means of HPLC. Results: During fluvoxamine use, the median of the total clearance of chloroguanide decreased in a statistically significant way from 1282 ml/min to 782 ml/min among the extensive metabolizers, whereas there was no change among the poor metabolizers. The partial clearance of chloroguanide by means of cycloguanil and 4-chlorphenylbiguanide formation among the extensive metabolizers decreased from 222 ml/min and 97 ml/min before to 33 ml/min and 11 ml/min during fluvoxamine intake, respectively. Among poor metabolizers the corresponding values were 35 ml/min and 7.6 ml/min before and 38 ml/min and 6.9 ml/min during fluvoxamine intake. for each metabolite clearance the change was statistically significant among the extensive metabolizers but not among the poor metabolizers. Both cycloguanil and 4-chlorphenylbiguanide formation clearances were statistically significantly higher among the extensive metabolizers than the poor metabolizers in period A but not in period B (phenocopy). Conclusion: Fluvoxamine is an effective inhibitor of CYP2C19.