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Vol. 27, Issue 1, 86-91, January 1999

In Vitro Metabolism of the HIV-1 Protease Inhibitor ABT-378: Species Comparison and Metabolite Identification

Gondi N. Kumar, Venkata Jayanti, Ronald D. Lee, David N. Whittern, John Uchic, Samuel Thomas, Paulette Johnson, Brian Grabowski, Hing Sham, David Betebenner, Dale J. Kempf, and Jon F. Denissen

Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois

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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.