Pharmacokinetics of Inhibitors of Succinyl-CoA:3-Ketoacid CoA Transferase in Sprague-Dawley Rats, and the Effect of a High-Fat Diet.

Pimozide and PSSI-51 are under study for their potential glucose-lowering effects in type 2 diabetes, through their abilities to inhibit succinyl-CoA:3-ketoacid CoA transferase, the rate-limiting enzyme of ketone oxidation. To understand their pharmacokinetics, they were administered to Sprague Dawley male and female rats after standard and high-fat diets. Initially five rats each were given 10 mg/kg of each agent orally, and using serial blood withdrawals from jugular vein cannulas, the blood samples were assayed for drug and basic pharmacokinetic data estimated using compartmental analysis. A separate group of male and female rats were given the same single dose after either 10 (pimozide) or 13 (PSSI-51) weeks of feeding with a standard or high-fat diet, followed by two blood samples after each dose from the saphenous vein. Bayesian forecasting in conjunction with the mean and variance of pharmacokinetic parameters and assay coefficient of variation, was used to estimate the pharmacokinetic parameters in these rats. The two drugs differed in their optimal pharmacokinetic model (pimozide one compartment, PSSI-51 two compartment). Both drugs possessed a high volume of distribution (Vd/F), but the oral clearance (CL/F) of PSSI-51 was much higher than that of pimozide, in line with earlier observations using rat microsomal experiments. The high-fat diet significantly reduced the oral CL and Vd of PMZ in both male and female rats, whereas no such effect was observed for PSSI-51.