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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Algorithms, Antimalarials, Aryl Hydrocarbon Hydroxylases, Chromatography, High Pressure Liquid, Cytochrome P-450 CYP2C19, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Enzyme Inhibitors, Fluvoxamine, Humans, In Vitro Techniques, Kinetics, Mitochondria, Liver, Mixed Function Oxygenases, Models, Biological, Proguanil, Serotonin Uptake Inhibitors.
user
Does fluvoxamine inhibit the CYP2C19-catalysed metabolism of proguanil in vitro? Context: 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. 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. 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.
assistant
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. Final Decision: yes