In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification.

Drug Metab Dispos. 1999 Jan;27(1):86-91. Unique Identifier : AIDSLINE MED/99102138
Kumar GN; Jayanti V; Lee RD; Whittern DN; Uchic J; Thomas S; Johnson P; Grabowski B; Sham H; Betebenner D; Kempf DJ; Denissen JF; Pharmaceutical Products Division, Abbott Laboratories, Abbott; Park, Illinois 60064-3500, USA. gondi.kumar@abbott.com

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.

Keywords: JOURNAL ARTICLE Animal Anti-HIV Agents/*METABOLISM Chromatography, High Pressure Liquid Comparative Study Dogs Female Human HIV Protease Inhibitors/*METABOLISM HIV-1/*ENZYMOLOGY Liver/CYTOLOGY/*METABOLISM Macaca fascicularis Male Mass Fragmentography Mice Microsomes, Liver/METABOLISM Middle Age Nuclear Magnetic Resonance Pyrimidinones/*METABOLISM Rats Rats, Sprague-Dawley
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