Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide

Clin Pharmacol Ther. 1997 Sep;62(3):279-86. doi: 10.1016/S0009-9236(97)90030-8.

Abstract

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).

Conclusion: Fluvoxamine is an effective inhibitor of CYP2C19.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antimetabolites / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases*
  • Biguanides / blood
  • Biguanides / urine
  • Biotransformation
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Fluvoxamine / pharmacology*
  • Folic Acid Antagonists / blood
  • Folic Acid Antagonists / urine
  • Humans
  • Male
  • Mephenytoin / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Proguanil / blood
  • Proguanil / pharmacokinetics*
  • Proguanil / urine
  • Serotonin Uptake Inhibitors / pharmacology*
  • Triazines / blood
  • Triazines / urine

Substances

  • Antimetabolites
  • Biguanides
  • Cytochrome P-450 Enzyme Inhibitors
  • Folic Acid Antagonists
  • Serotonin Uptake Inhibitors
  • Triazines
  • cycloguanil
  • 4-chlorophenylbiguanide
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Fluvoxamine
  • Mephenytoin
  • Proguanil