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CDRI 99/411 is a potent 1,2,4-trioxane anti-malarial candidate compound of the Central Drug Research Institute, India. This study aimed to conduct comprehensive in vitro metabolic investigations of CDRI 99/411 to corroborate its preclinical investigations. Preliminary in vitro metabolic investigations were performed to assess the metabolic stability [in vitro half-life (t1/2) and in vitro hepatic intrinsic clearance (Clint)] of CDRI 99/411 in male Sprague–Dawley rat and human liver microsomes using validated high-performance liquid chromatography with photodiode array detector. The observed in vitro t1/2 of the compound in rat and human liver microsomes was 13 min with in vitro Clint 130.7 ± 25.0 μL/min/mg and 19 min with in vitro Clint 89.3 ± 17.40 μL/min/mg. These observations suggested moderate metabolic degradation and in vitro Clint with insignificant difference (p > 0.05) in the metabolic stability profile in rat and human. Hence, in vitro metabolic investigations were performed with rat liver microsomes. It was observed that CDRI 99/411 exhibited sigmoidal kinetics. At nonlinear regression (r ≥ 0.99) EC50 and Hill slope values were 17 µm and 1.50, respectively. The metabolism of CDRI 99/411 was primarily mediated by CYP3A2 and was inferred by CYP reaction phenotyping with known potent inhibitors. Two metabolites of CDRI 99/411 were detected which were undetectable on incubation with 1-aminobenzotriazole and ketoconazole. Copyright © 2011 John Wiley & Sons, Ltd.

A rapid, sensitive and selective LC-MS/MS method for the quantitative analysis of 3-hydroxy pterocarpan (S006-1709) in female rat plasma has been developed and validated. A Discovery RP18 column was used for the chromatographic elution using acetonitrile and 0.1% acetic acid in water as mobile phase (80:20 v/v) at the flow rate of 0.5 mL/min. MS/MS analysis was performed using a triple quadrupole mass spectrometer with electrospray ionization in negative ion mode using biochanin as an internal standard (IS). Extraction of S006-1709 and IS from rat plasma was done by liquid–liquid extraction method using diethyl ether. The LC-MS/MS method was sensitive with 1.95 ng/mL as the limit of detection and 3.9 ng/mL as the lower limit of quantification. The method was linear in the concentration range of 3.9–1000 ng/mL. The percentage bias for intraday and interday accuracy was not greater than 4.2 and the %RSD for intraday and interday precision was not greater than 13.2. The recoveries of S006-1709 and IS were 73.9–79.3 and 85.7%, respectively. S006-1709 was found to be stable in various stability studies. The validated LC-MS/MS method was successfully applied for the oral pharmacokinetics study of S006-1709 at 10 mg/kg in female Sprague–Dawley rats. Copyright © 2010 John Wiley & Sons, Ltd.