Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro

Eur J Clin Pharmacol. 1998 Nov-Dec;54(9-10):735-40. doi: 10.1007/s002280050544.


Objective: The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro.

Methods: A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I.

Results: The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. Fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19.

Conclusions: Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine, clomipramine, amitriptyline and diazepam. The combination of fluvoxamine and proguanil can not be recommended.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antimalarials / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Fluvoxamine / pharmacology*
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / enzymology
  • Mitochondria, Liver / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Models, Biological
  • Proguanil / metabolism*
  • Selective Serotonin Reuptake Inhibitors / pharmacology*


  • Antimalarials
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Serotonin Uptake Inhibitors
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Fluvoxamine
  • Proguanil