Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009-0629 in rats.

S009-0629 [methyl-8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009-0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC-MS/MS) method. The plasma protein binding of S009-0629 using modified charcoal adsorption method at 5 and 10 mu g/mL was 80.58 +/- 1.04% and 81.95 +/- 1.15%, respectively. The K-RBC/PL of S009-0629 was independent of concentration and time. The in-vitro half-life of S009-0629 at 5 and 10 mu M using rat liver microsomes was determined as 273 +/- 24.46 and 281.67 +/- 26.53 min, respectively. After oral administration, S009-0629 exhibited C-max 55.51 +/- 1.18 ng/mL was observed at 18 hr (t(max)). S009-0629 was found to have the large apparent volume of distribution (1,894.93 +/- 363.67 L/kg). Oral in-vivo t(1/2) of S009-0629 was found to be 41.23 +/- 5.96 hr. A rapid and highly sensitive LC-MS/MS method was validated for S009-0629 in rat plasma. S009-0629 has high plasma protein binding and low hepatic extraction. S009-0629 has no affinity with human P-gp and BCRP in ATPase assay. After oral dosing, S009-0629 has slow absorption and elimination in rats.