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 develop ed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from pr oguanil 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 al most exclusively catalysed by a single enzyme, i.e. CYP2C19 within the conc entration range used, or that the contribution of an alternative low-affini ty enzyme, probably CYP3A4, is very low. This notion was confirmed by the l ack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocrip tine, midazolam and dihydroergotamine. Fluvoxamine was a very effective inh ibitor of the oxidation of proguanil, displaying K-i values of 0.69 mu mol. l(-1) for the inhibition of cycloguanil formation and 4.7 mu mol.l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omep razole inhibited the formation of both metabolites with an IC50 of 10 mu mo l.l(-1) Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with K-i values of 7.3-16 mu mol.l(-1), suggesting that the two compounds are m oderate 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 CYP2C 19 such as imipramine, clomipramine, amitriptyline and diazepam. The combin ation of fluvoxamine and proguanil can not be recommended.