Metabolism and excretion of ( S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1 H-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

Xenobiotica. 2019 Dec;49(12):1447-1457. doi: 10.1080/00498254.2019.1581960. Epub 2019 Mar 7.


1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [14C]-(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-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 (M2a-d). Unchanged PF-04991532 was the major circulating component (64.4% of total radioactivity) whereas M2a-d collectively represented 28.9% of the total plasma radioactivity. 3. Metabolites M2a-d 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 M2a-d 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 M2a-d. 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.

Keywords: CYP; Glucokinase; MIST; activator; disproportionate; human; mass balance; metabolite; monkey; radiolabel; safety.

Publication types

  • Clinical Trial
  • Video-Audio Media

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Carbon Radioisotopes / administration & dosage
  • Carbon Radioisotopes / pharmacokinetics
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Feces / chemistry
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics*
  • Inactivation, Metabolic
  • Macaca fascicularis
  • Male
  • Middle Aged
  • Nicotinic Acids / metabolism
  • Nicotinic Acids / pharmacokinetics*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Young Adult


  • Carbon Radioisotopes
  • Imidazoles
  • Nicotinic Acids
  • Recombinant Proteins
  • Carbon-14
  • Cytochrome P-450 Enzyme System
  • 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid