THE RAT BILIARY METABOLITES OF DIHYDROARTEMISININ, AN ANTIMALARIAL ENDOPEROXIDE

[13-C-14]Dihydroartemisinin was administered to male rats (35 mu mol k g(-1), iv). Within 0-1 hr and 0-5 hr of dosing, 34.8 +/- 5.2% (mean +/ - SD, N = 6) and 48.4 +/- 5.9% of the radiolabel, respectively, was re covered in bile. Only 1.1 +/- 1.2% was recovered in bladder urine afte r 5 hr. The biliary metabolites were identified by LC/MS. The principa l metabolite (21.1 +/- 9.3% of dose) was the biologically inactive dih ydroartemisinin (DHA) glucuronide. The other metabolites were products of reductive cleavage and rearrangement of the endoperoxide bridge, a process known to generate reactive radical intermediates and abolish antimalarial activity. They were desoxy-DHA (3.3 +/- 2.0%) and its glu curonide (1.1 +/- 1.0%), 3-hydroxydesoxy-DHA glucuronide (2.9 +/- 1.8% ), and the glucuronide of a ring-contracted tetrahydrofuran acetate is omer of DHA (6.9 +/- 5.6%).