title: In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification.
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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. gondi.kumar@abbott.com
authors.forename: G N
authors.initials: GN
authors.lastname: Kumar
authors.forename: V
authors.initials: V
authors.lastname: Jayanti
authors.forename: R D
authors.initials: RD
authors.lastname: Lee
authors.forename: D N
authors.initials: DN
authors.lastname: Whittern
authors.forename: J
authors.initials: J
authors.lastname: Uchic
authors.forename: S
authors.initials: S
authors.lastname: Thomas
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.forename: B
authors.initials: B
authors.lastname: Grabowski
authors.forename: H
authors.initials: H
authors.lastname: Sham
authors.forename: D
authors.initials: D
authors.lastname: Betebenner
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: J F
authors.initials: JF
authors.lastname: Denissen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D061466:Lopinavir; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D011744:Pyrimidinones / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir