PT  - JOURNAL ARTICLE
AU  - James L. Maggs
AU  - Laurence P. D. Bishop
AU  - Geoffrey Edwards
AU  - Paul M. O'Neill
AU  - Stephen A. Ward
AU  - Peter A. Winstanley
AU  - B. Kevin Park
TI  - Biliary Metabolites of β-Artemether in Rats: Biotransformations of an Antimalarial Endoperoxide
DP  - 2000 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 209--217
VI  - 28
IP  - 2
4099  - http://dmd.aspetjournals.org/content/28/2/209.short
4100  - http://dmd.aspetjournals.org/content/28/2/209.full
SO  - Drug Metab Dispos2000 Feb 01; 28
AB  - β-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 kg−1, 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 9α-hydroxyAM (33.4 ± 6.8% biliary radioactivity) and α-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, 9α-hydroxyAM, is unlikely to possess significant antimalarial activity. The American Society for Pharmacology and Experimental Therapeutics