Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct‐cannulated rats

The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and 14C‐TDP223206 were administered to intact and bile duct‐cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUCinf increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254–386 ml/h/kg) and a moderate volume of distribution (968–1883 ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50 mg/kg oral doses, respectively. 14C‐TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. 14C‐TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of 14C‐TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. 14C‐TDP223206‐acyl glucuronides were the major metabolites in bile. The oxo‐14C‐TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of 14C‐TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these 14C‐TDP223206‐acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo‐isomers. Copyright © 2008 John Wiley & Sons, Ltd.