Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro

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^-1 · h^-1. 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 K₁ values of 0.69 μmol · l^-1 for the inhibition of cycloguanil formation and 4.7 μmol · 1^-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 μmol · 1^-1. Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with K₁ values of 7 3-16 μmol · 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.