Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR‐dual activator in rats

Abstract

Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats.