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

Abstract

The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and (14)C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUC(inf) 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. (14)C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. (14)C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of (14)C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. (14)C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo-(14)C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of (14)C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these (14)C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers.

Addressing the analytical throughput challenges in ADME screening using rapid ultra‐performance liquid chromatography/tandem mass spectrometry methodologies

“…High‐performance liquid chromatography with either optical or mass spectrometric detection (HPLC/MS(MS)) has become an essential part of the drug discovery and development analytical arsenal 10–12. HPLC and LC/MS are used to check for product purity, product assay, to determine the pharmacokinetics of an NCE, and identify degradation products amongst other numerous tasks 13–17. The specificity derived from the LC separation and MS selectivity makes LC/MS an ideal candidate as an analytical tool for large‐scale ADME screening.…”