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Open Access Comparative Analysis of In Vitro Rat Liver Metabolism of the Antimalarial Primaquine and a Derived Imidazoquine

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The present study provides proof-of-concept regarding the expectedly high enzymatic stability of primaquinederived imidazolidin-4-ones, imidazoquines, formerly developed as alternatives to the parent antimalarial with potentially improved oral bioavailability [J. Med. Chem., 2009, 52, 7800-7807]. This study provides relevant experimental evidence on the remarkably low propensity of imidazoquines to undergo metabolic conversions mediated by rat liver enzymes. This, together with favourable key ADME parameters previously predicted for these compounds [Bioorg. Med. Chem. Lett. 2009, 19, 6914-6917], and proven lack of acute toxicity in mice, further reinforces the role of imidazoquines as reference leads for the development of novel primaquine surrogates. This is a particularly relevant issue in the present status of malaria chemotherapy worldwide, where primaquine remains the sole drug in clinical use able to block transmission between infected persons and the insect vector and to effectively act on liver-stage parasite forms, including hypnozoites.

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Keywords: Antimalarial; Carboxyprimaquine; DMSO; Derived Imidazoquine; Heinz-body anaemia; Liver Metabolism; NADH; Primaquine; Toxic hydroxylated metabolites; hypnozoites

Document Type: Research Article

Publication date: March 1, 2012

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  • Drug Metabolism Letters publishes short papers on major advances in all areas of drug metabolism and disposition. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly by taking full advantage of the Internet technology for both the submission and review of manuscripts. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites, reactive intermediate and glutathione conjugates.
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