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In vitro Biopharmaceutic Assessment, Intravenous Pharmacokinetics and Oral Bioavailability of a Novel Anti-malarial Lead S011-1793

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Background: Malaria remains one of the most devastating infectious diseases with approximately 212 million infections and 429,000 deaths each year. Resistance to antimalarial drugs has often jeopardized malaria elimination efforts and has led to resurgence of malaria incidences and deaths. To embark upon the challenges of the resistance, alternate therapies and newer drugs need to be brought into market. CSIR-Central Drug Research Institute is moving forward for the same and identified a novel anti-malarial lead CDRI-S011-1793 which was found to be active even in multi drug resistant malaria strain models. The potential lead is in preclinical lead optimization stage. Materials and Methods: In vitro pH stability (simulated gastrointestinal fluid), metabolic stability, plasma stability and plasma protein binding studies were performed. In vivopharmacokinetic studies were also conducted in male Sprague Dawely rats at 2 and 20 mg/kg upon intravenous and per-oral routes of administration respectively. Blood samples were collected up to 48hr, plasma was separated and used for further bio-analysis by validated LC-MS/MS method. The data analysis was carried out usingusing WinNonlin (version 5.1, Pharsight Corporation, USA). Results and Conclusions: S011-1793 was found to be stable in both simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) up to 2h. The compound was found to be 96.13±0.07% stable in plasma up to 2h. Protein binding was found to be 71.51±0.67%. In vitro metabolic assays delineated that is a high clearance compound as itsClin vitro was estimated to be 176.4ml/min*kg. Upon intravenous administration, the apparent volume of distribution (Vd) and clearance (Cl) were estimated to be 265.139±19.524L/kg and 207.438±28.672 mL/min/kg, respectively. The larger value of Vd indicates its high peripheral distribution. The plasma half-life and elimination rate constant were found to be 14.944±2.461h and 0.047±0.008 h-1, respectively. Upon oral administration, the systemic exposure was estimated to be 583.96±30.35 hr*ng/mL. The absolute oral bioavailability (%F) was found to be 64.46%.