Add time:07/21/2019         Source:sciencedirect.com

Arteflene is a synthetic endoperoxide antimalarial. Its peroxide bridge undergoes iron(II)-mediated reduction in vitro which yields a carbon-centered cyclohexyl radical and a mixture of cis- and trans-α,β-unsaturated ketones (enones). The enones are biliary metabolites in rats and therefore surrogate markers of bioactivation. Arteflene is reported to be more cytotoxic to primary rat hepatocytes than some non-endoperoxide antimalarials. Hepatic metabolism of arteflene was investigated in recirculating isolated perfused rat livers, and the drug’s metabolism and cytotoxicity were compared using hepatocytes from male rats. Both preparations metabolized [14C]arteflene to cis- and trans-[14C]enone, 8-hydroxyarteflene glucuronide and an unassigned isomeric glucuronide. During a 2 h liver perfusion, the cis- and trans-enones recovered in bile represented 8.1±3.4 and 11.3±4.6% (mean±S.D., N=6), respectively, of the [14C]arteflene (52 μM) added to the perfusate. After a 3 h incubation of [14C]arteflene (10 μM) with hepatocytes in suspension, the cis- and trans-enones comprised, respectively, 14.8±7.1 and 2.1±1.0% (N=4) of the recovered radioactivity; the corresponding data for cultured hepatocytes being 18.6±6.9 and 3.3±2.2%. Arteflene was significantly (P<0.05) toxic to isolated hepatocytes with reference to extramitochondrial reductase activity (tetrazolium reduction) but not enzyme leakage when the cells were exposed to drug concentrations ≥50 μM for 24 h. Cellular glutathione was depleted under these conditions. Therefore arteflene was acutely cytotoxic, though only at relatively high concentrations, when it was metabolized via a pathway which generates carbon-centered radicals.

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