Vol. 289, Issue 1, 511-520, April 1999

Metabolism of the Antimalarial Endoperoxide Ro 42-1611 (Arteflene) in the Rat: Evidence for Endoperoxide Bioactivation¹

Laurence P. D. Bishop, James L. Maggs, Paul M. O'Neill and B. Kevin Park

Departments of Pharmacology and Therapeutics (L.P.D.B., J.L.M., B.K.P.) and Chemistry (P.M.O.), University of Liverpool, Liverpool, United Kingdom

Ro 42-1611 (arteflene) is a synthetic endoperoxide antimalarial. The antimalarial activity of endoperoxides is attributed to iron(II)-mediated generation of carbon-centered radicals. An ,-unsaturated ketone (enone; 4-[2',4' bis(trifluoromethyl)phenyl]-3-buten-2-one), obtained from arteflene by reaction with iron(II), was identified previously as the stable product of a reaction that, by inference, also yields a cyclohexyl radical. The activation of arteflene in vivo has been characterized with particular reference to enone formation. [¹⁴C]Arteflene (35 µmol/kg) was given i.v. to anesthetized 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, the 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) of the radiolabel was recovered in urine over 24 h. The principal urinary metabolite appeared to be a glycine conjugate of a derivative of the enone. Biliary excretion of the glucuronide, but not of the enones, was inhibited by ketoconazole. 8-Hydroxyarteflene was formed extensively by rat and human liver microsomes but no enone was found. Bioactivation is a major pathway of arteflene's metabolism in the rat. Although the mechanism of in vivo bioactivation is unclear, the reaction is not catalyzed by microsomal cytochrome P-450 enzymes.