The rat biliary metabolites of dihydroartemisinin, an antimalarial endoperoxide.
[13-14C]Dihydroartemisinin was administered to male rats (35 micromol kg-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 recovered in bile. Only 1.1 +/- 1.2% was recovered in bladder urine after 5 hr. The biliary metabolites were identified by LC/MS. The principal metabolite (21.1 +/- 9.3% of dose) was the biologically inactive dihydroartemisinin (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 glucuronide (1.1 +/- 1.0%), 3-hydroxydesoxy-DHA glucuronide (2.9 +/- 1.8%), and the glucuronide of a ring-contracted tetrahydrofuran acetate isomer of DHA (6.9 +/- 5.6%).
Maggs
J L
JL
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Madden
S
S
Bishop
L P
LP
O'Neill
P M
PM
Park
B K
BK
D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins; D001646:Bile / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000378:metabolism*
D000962:Antimalarials; D037621:Artemisinins; D002250:Carbon Radioisotopes; D012717:Sesquiterpenes; C039060:artenimol