PF-05175157

The in vitro metabolism of PF-05175157 is evaluated in microsomes from rat, dog, and human hepatocytes. This compound is not metabolized in rat, dog, or human microsomes. It is also stable in human hepatocyte incubations, but is minimally metabolized by recombinant human CYP3A4 and CYP3A5, suggesting it is a substrate for CYP3A4 and CYP3A5. This chemical inhibits formation of malonyl-CoA in a concentration-dependent manner with a potency (EC50 = 30 nM) in rat hepatocytes consistent with its potency against rat ACC1 (24 nM).^[1]

On the day of the study, media was aspirated and cells are treated with fresh MCM media containing DMSO vehicle or varying concentrations of PF-05175157 as indicated. This compound was initially dissolved in DMSO and subsequently diluted 1:100 in MCM.After 5 h at 37 °C, incubation media is removed and the experiment is terminated by washing the cells with ice cold PBS.

In vivo, the plasma clearance of PF-05175157 is low following intravenous (iv) administration (1 mg/kg) to rats, dogs, and monkeys. Oral (po) administration (3 mg/kg) to rats and dogs showed bioavailability of 40% and 54%, respectively, consistent with the low microsomal clearance and good solubility at low pH. The bioavailability following a 50 mg/kg oral dose in rats was 106%, suggesting saturation of clearance. Formation of the direct product of ACC, malonyl-CoA, in the skeletal muscle and liver of lean Sprague Dawley rats is assessed 1 h following an acute oral dose of this compound, showing concentration-dependent reductions in both skeletal muscle and liver malonyl-CoA. At the nadir, quadriceps and liver malonyl-CoA levels are reduced by 76% and 89%, respectively. ^[1]