| Popis: |
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. |
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