Oral bioavailability and Pharmacokinetics of PAT-5A, a new insulin sensitizer in rats

Pharmacokinetics of PAT-5A (a new thiazolidinedione derivative), a potent insulin sensitizing and lipid-lowering compound was studied in rats. A single dose of 3, 10, 30 and 100 mg/kg PAT-5A was given orally to Wistar rats for investigating the dose linearity in pharmacokinetics. In another study, a single intravenous bolus dose of PAT-5A was given to rats at 10 mg/kg dose following administration through the tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and concentration of PAT-5A in plasma was determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v. dosing and subjected to noncompartment pharmacokinetic analysis to obtain the values for the parameters. Both Cmax and AUC0-infinity appeared to increase proportionally to the administered oral doses. While the doses increased in the ratio of 1.0:3.3:10.0:33.3, the mean Cmax and AUC0-infinity increased in the ratio of 1.0:3.3:8.0:16.7 and 1:4.4:12.0:32.1, respectively. The systemic clearance and volume of distribution of PAT-5A in rats were 83.1 mL/h and 177.1 mL respectively after i.v. administration. Plasma concentrations declined monoexponentially following oral as well as intravenous administration and terminal half-life was about 1.4 h. There was no significant change in half-life with increase in oral doses. Absolute oral bioavailability of PAT-5A across the doses tested was in the range of 73-100% and this indicates that PAT-5A is neither a candidate for pre-systemic metabolism nor prone to absorption-related issues.