Abstract
[13-14C]Dihydroartemisinin was administered to male rats (35 μmol 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%).
Footnotes
-
Send reprint requests to: Dr. B. Kevin Park, Department of Pharmacology and Therapeutics, University of Liverpool, Ashton Street, Liverpool L69 3BX, UK.
-
P.M.O. and L.P.B. were supported by Roche (Welwyn) and the Wellcome Trust, respectively.
-
Present address for S. Madden: Inveresk Research International Ltd., Tranent, Scotland.
-
↵2 J. L. Maggs et al., unpublished data.
- Abbreviations used are::
- DHA
- dihydroartemisinin
- THF
- tetrahydrofuran
- [14C]DHA
- [13-14C]dihydroartemisinin
- DIBAL-H
- diisobutylaluminum hydride
- ESP
- electrospray
- CID
- collision-induced decomposition
- SIM
- selected ion monitoring
- Received September 27, 1996.
- Accepted July 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|