Metabolism of the antimalarial endoperoxide Ro 42-1611 (arteflene) in the rat: Evidence for endoperoxide bioactivation

Ro 42-1611 (arteflene) is a synthetic endoperoxide antimalarial. The antima larial activity of endoperoxides is attributed to iron(II)-mediated generat ion of carbon-centered radicals. An alpha,beta-unsaturated ketone (enone; 4 -[2',4' bis(trifluoromethyl)phenyl]3-buten-2-one), obtained from arteflene by reaction with iron(ll), was identified previously as the stable product of a reaction that, by inference, also yields a cyclohexyl radical. The act ivation of arteflene in vivo has been characterized with particular referen ce to enone formation. [C-14]Arteflene (35 mu mol/kg) was given i.v. to ane sthetized and cannulated male rats: 42.2 +/- 7.0% (mean +/- S.D., n = 7) of the radiolabel was recovered in bile over 5 h. In the majority of rats, th e principal biliary metabolites were 8-hydroxyarteflene glucuronide (14.2 /- 3.9% dose, 0-3 h) and the cis and trans isomers of the enone (13.5 +/- 4 .6% dose, 0-3 h). In conscious rats, 15.3 +/- 1.6% (mean +/- S.D., n = 8) o f the radiolabel was recovered in urine over 24 h. The principal urinary me tabolite appeared to be a glycine conjugate of a derivative of the enone. B iliary excretion of the glucuronide, but not of the enones, was inhibited b y ketoconazole. 8-Hydroxyarteflene was formed extensively by rat and human liver microsomes but no enone was found. Bioactivation is a major pathway o f arteflene's metabolism in the rat. Although the mechanism of in vivo bioa ctivation is unclear, the reaction is not catalyzed by microsomal cytochrom e P-450 enzymes.