Determination of metabolic profile of anti-malarial trioxane CDRI 99/411 in rat liver microsomes using HPLC

✍ Scribed by Smriti Mishra; Lakshmi Manickavasagam; Girish Kumar Jain

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 429 KB
• Volume: 26
• Category: Article
• ISSN: 0269-3879
• DOI: 10.1002/bmc.1635

✦ Synopsis

ABSTRACT

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 (t~1/2~) and in vitro hepatic intrinsic clearance (Cl~int~)] 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 t~1/2~ of the compound in rat and human liver microsomes was 13 min with in vitro Cl~int~ 130.7 ± 25.0 μL/min/mg and 19 min with in vitro Cl~int~ 89.3 ± 17.40 μL/min/mg. These observations suggested moderate metabolic degradation and in vitro Cl~int~ 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) EC~50~ 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.