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 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).


CONCLUSIONS
Fluvoxamine is an effective inhibitor of CYP2C19.
Jeppesen
U
U
Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Denmark. u.jeppesen@winsloew.ou.dk
Rasmussen
B B
BB
Brøsen
K
K
D000284:Administration, Oral; D000328:Adult; D000963:Antimetabolites / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001645:Biguanides / Q000097:blood / Q000652:urine; D001711:Biotransformation; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000097:blood / Q000652:urine; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002727:Proguanil / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014227:Triazines / Q000097:blood / Q000652:urine
D000963:Antimetabolites; D001189:Aryl Hydrocarbon Hydroxylases; D001645:Biguanides; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D016666:Fluvoxamine; D005493:Folic Acid Antagonists; D008617:Mephenytoin; D006899:Mixed Function Oxygenases; D002727:Proguanil; D017367:Selective Serotonin Reuptake Inhibitors; D014227:Triazines; C026009:cycloguanil; C025963:4-chlorophenylbiguanide; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human