Abstract
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 Ki values of 0.69 μmol · l−1 for the inhibition of cycloguanil formation and 4.7 μmol · 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 μmol · l−1. Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki 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.
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Received: 28 February 1998 / Accepted: 2 June 1998
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Buur Rasmussen, B., Nielsen, T. & Brøsen, K. Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. E J Clin Pharmacol 54, 735–740 (1998). https://doi.org/10.1007/s002280050544
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DOI: https://doi.org/10.1007/s002280050544