Vol. 28, Issue 2, 209-217, February 2000

Biliary Metabolites of -Artemether in Rats: Biotransformations of an Antimalarial Endoperoxide

James L. Maggs, Laurence P. D. Bishop, Geoffrey Edwards, Paul M. O'Neill, Stephen A. Ward, Peter A. Winstanley, and B. Kevin Park

Departments of Pharmacology and Therapeutics (J.L.M., L.P.D.B., G.E., S.A.W., P.A.W., B.K.P.) and Chemistry (P.M.O'N.), University of Liverpool; and Division of Parasite and Vector Biology, Liverpool School of Tropical Medicine (G.E.), Liverpool, United Kingdom.

-Artemether (AM), the O-methyl ether prodrug of dihydroartemisinin (DHA), is an endoperoxide antimalarial. The biliary metabolites of AM in adult male Wistar rats were characterized with particular reference to potential antimalarial compounds and stable derivatives of free radical intermediates. [13-¹⁴C]-AM (35 µmol kg¹, i.v.) was administered to anesthetized rats. Within 0 to 3 h, 38.6 ± 4.8% (mean ± S.D., n = 6) of the radiolabel was recovered in bile; the 0- to 5-h recovery was 42.3 ± 4.3%. The major metabolites (0-3 h) were the glucuronides of 9-hydroxyAM (33.4 ± 6.8% biliary radioactivity) and -DHA (22.5 ± 4.4%); four stereochemically unassigned monohydroxyAM glucuronides (II, 3.1 ± 0.9; IV, 4.4 ± 1.7%; V, 21.4 ± 3.0%; VI, 3.0 ± 1.1%) and a dihydroxyAM glucuronide (6.0 ± 2.1%) were also identified. A sixth monohydroxyAM glucuronide (VIIa) and desoxyDHA glucuronide were detected in trace amounts. The furano acetate isomer of DHA glucuronide, indicative of the formation of a radical intermediate, was also found in trace amounts. O-methyl substitution of DHA favors ring hydroxylation in vivo. However, the principal hydroxylated metabolite, 9-hydroxyAM, is unlikely to possess significant antimalarial activity.