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

HIV protease inhibitor ABT-378 (ABT-378) was metabolized very extensively a nd rapidly by liver microsomes from mouse, rat, dog, monkey, and humans. Th e rates of NADPH-dependent metabolism of ABT-378 ranged from 2.39 to 9.80 n mol mg microsomal protein(-1) min(-1), with monkey liver microsomes exhibit ing the highest rates of metabolism. ABT-378 was metabolized to 12 metaboli tes (M-1 to M-12), which were characterized by mass and NMR spectroscopy. T he 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 min or 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-hyd roxy-ABT-378) was formed by rodents at a faster rate than by dog, monkey, a nd human liver microsomes, Metabolites M-5 to M-8 were identified as monohy droxylated derivatives of ABT-378. Metabolites M-9 and M-10 were identified as hydroxylated products of M-l, Metabolites Arl-ll and M-12 were identifi ed as dihydroxylated derivatives of ABT-378, The metabolite profile in huma n hepatocytes and river slices was similar to that of human river microsome s, The results of the current study indicate that ABT-378 is highly suscept ible to oxidative metabolism in vitro, and possibly in vivo, in humans.