FLUVOXAMINE INHIBITS THE CYP2C19-CATALYZED BIOACTIVATION OF CHLOROGUANIDE

Objective: To investigate the interaction between fluvoxamine and chlo roguanide (INN, proguanil) to confirm that fluvoxamine inhibits CYP2C1 9. Methods: The study was carried out with a randomized, in vivo, cros sover design. Six volunteers were extensive metabolizers of the S-meph enytoin oxidation polymorphism, and six volunteers were poor metaboliz ers. 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 da ys 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 u rine were assayed by means of HPLC. Results: During fluvoxamine use, t he median of the total clearance of chloroguanide decreased in a stati stically significant way from 1282 ml/min to 782 ml/min among the exte nsive metabolizers, whereas there was no change among the poor metabol izers. 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 t he 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 cle arance the change was statistically significant among the extensive me tabolizers but not among the poor metabolizers. Both cycloguanil and 4 -chlorphenylbiguanide formation clearances were statistically signific antly higher among the extensive metabolizers than the poor metabolize rs in period A but not in period B (phenocopy). Conclusion: Fluvoxamin e is an effective inhibitor of CYP2C19.