Abstract
HIV protease inhibitor ABT-378 (ABT-378) was metabolized very extensively and rapidly by liver microsomes from mouse, rat, dog, monkey, and humans. The rates of NADPH-dependent metabolism of ABT-378 ranged from 2.39 to 9.80 nmol·mg microsomal protein−1·min−1, with monkey liver microsomes exhibiting the highest rates of metabolism. ABT-378 was metabolized to 12 metabolites (M-1 to M-12), which were characterized by mass and NMR spectroscopy. The metabolite profile of ABT-378 in liver microsomes from all five species was similar, except that the mouse liver microsomes did not form M-9, a minor secondary metabolite. The predominant site of metabolism was the cyclic urea moiety of ABT-378. In all five species, the major metabolites were M-1 (4-oxo-ABT-378) and M-3 and M-4 (4-hydroxy-ABT-378). Metabolite M-2 (6-hydroxy-ABT-378) was formed by rodents at a faster rate than by dog, monkey, and human liver microsomes. Metabolites M-5 to M-8 were identified as monohydroxylated derivatives of ABT-378. Metabolites M-9 and M-10 were identified as hydroxylated products of M-1. Metabolites M-11 and M-12 were identified as dihydroxylated derivatives of ABT-378. The metabolite profile in human hepatocytes and liver slices was similar to that of human liver microsomes. The results of the current study indicate that ABT-378 is highly susceptible to oxidative metabolism in vitro, and possibly in vivo, in humans.
Footnotes
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Send reprint requests to: Gondi N. Kumar, D46V, AP9, Abbott Laboratories, Abbott Park, IL 60064-3500. E-mail:gondi.kumar{at}abbott.com
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This work was presented as a poster at the 8th North American ISSX Meeting, Hilton Head, SC, Abstract 94.
- Abbreviations used are::
- AUC
- area under the plasma concentration-time curve
- HPLC
- high-performance liquid chromatography
- CYP
- cytochrome
- Received May 7, 1998.
- Accepted August 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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