Metabolism and excretion of ()-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, in humans: confirmation of the MIST potential noted in first-in-Human metabolite scouting studies.

1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [C]-()-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, was investigated in humans. Mass balance was achieved with ∼94.6% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 70.6% and 24.1%, respectively. Unchanged PF-04991532 collectively accounted for ∼47.2% of the dose excreted in feces and urine, suggestive of moderate metabolic elimination in humans. 2. The biotransformation pathways involved acyl glucuronidation (M1), amide bond hydrolysis (M3), and CYP3A4-mediated oxidative metabolism on the cyclopentyl ring in PF-04991532 yielding monohydroxylated isomers (M2-). Unchanged PF-04991532 was the major circulating component (64.4% of total radioactivity) whereas M2- collectively represented 28.9% of the total plasma radioactivity. 3. Metabolites M2- were not detected systemically in rats and dogs, the preclinical species for the toxicological evaluation of PF-04991532. In contrast, cynomologus monkeys dosed orally with unlabeled PF-04991532 revealed M2- in circulation, whose UV abundance was comparable to the profile in humans. This observation suggested that monkeys could potentially serve as a non-rodent alternative for studying the toxicity of PF-04991532 and its metabolites M2-. 4. The present results are in excellent agreement with our previously generated metabolite scouting data, which provided preliminary evidence for the disproportionate metabolism of PF-04991532 in humans.