title: Pharmacokinetic studies of a novel trioxane antimalarial (99/411) in rats and monkeys using LC-MS/MS.
abstract: The pharmacokinetic profile of 99/411, a novel anti-malarial drug, was established in rats (12 mg/kg of body weight) and monkeys (20 mg/kg of body weight). Following oral administration, the presence of 99/411 was rapidly determined in rat plasma, tissues, urine, feces and monkey plasma using a validated LC-MS/MS method. The tissue distribution studies in rats indicated that the drug was partially distributed in all major tissues and plasma, and peak concentration levels were achieved within 0.5-4 h. Area under the curve in different rat tissues and plasma was found in order of blood > lung > intestine > heart > muscle > brain > kidney > spleen > liver. The total recoveries (within 86 h) of 99/411 were <0.0017% and <0.08% in urine and feces, respectively. The peak plasma concentration was 3499 ng/mL in rats after ~2 h of oral administration and 697-767 ng/mL in monkeys after ~6 h of oral administration. No plasma accumulation was observed in both male and female monkeys, even after multiple dosing. The preclinical pharmacokinetic profile and tissue distribution data are expected to assist in future clinical explorations of 99/411 as a promising anti-malarial agent.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, UP, Lucknow, India.|School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Pandey
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, UP, Lucknow, India.|Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Nebraska, Omaha, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, UP, Lucknow, India.
authors.forename: Hari Narayan
authors.initials: HN
authors.lastname: Kushwaha
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, UP, Lucknow, India.
authors.forename: Shio Kumar
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid / Q000379:methods*; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution
chemical_list: C529215:99-411 compound; D000962:Antimalarials; D006571:Heterocyclic Compounds; D013141:Spiro Compounds
keywords: LC-MS/MS; anti-malarial; excretion; pharmacokinetics; tissue distribution