Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that shows key involvement in age-related disease and promises to be target for treatment of cancer. In the present study the elimination of potent ATP-competitive mTOR inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. Compound 1 was shown to undergo extensive N-glucuronidation in bile duct catheterized (BDC) rats. N-glucuronides were detected on positions N1 (M2) and N2 (M1) of the pyrazole moiety as well as on the primary amine (M3). All three N-glucuronide metabolites were detected in liver microsomes of the rat, dog and human, while primary amine glucuronidation was not detected in non-human-primate (NHP). In addition N1 and N2-glucuronidation showed strong species selectivity in vitro, with rats, dogs and humans favoring N2-glucuronidation and NHPs favoring N1-glucuronide formation. Formation of M1 in NHP liver microsomes also followed sigmoidal kinetics, singling out NHP as unique among the species with regard to compound 1 N-glucuronidation. In this respect, NHP might not always be the best animal model for N-glucuronidation of UGT1A9 or UGT1A1 substrates in humans. Impact of N-glucuronidation of compound 1 could be more pronounced in higher species such as NHP and human leading to high clearance in these species. While compound 1 shows promise as a candidate for investigating the impact of pan-mTOR inhibition in vivo, opportunities may exists through medicinal chemistry effort to reduce metabolic liability with the goal of improving systemic exposure.
- The American Society for Pharmacology and Experimental Therapeutics