fluvoxamine and 4-chlorophenylbiguanide

To investigate the interaction between fluvoxamine and chloroguanide (INN, proguanil) to confirm that fluvoxamine inhibits CYP2C19.. 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.. 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 cydoguanil 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).. Fluvoxamine is an effective inhibitor of CYP2C19.

Topics: Administration, Oral; Adult; Antimetabolites; Aryl Hydrocarbon Hydroxylases; Biguanides; Biotransformation; Cross-Over Studies; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Fluvoxamine; Folic Acid Antagonists; Humans; Male; Mephenytoin; Mixed Function Oxygenases; Proguanil; Selective Serotonin Reuptake Inhibitors; Triazines