title: Pharmacokinetic study of the novel, synthetic trioxane antimalarial compound 97-78 in rats using an LC-MS/MS method for quantification.
abstract: The present study has been designed to investigate the pharmacokinetic parameters of the novel trioxane antimalarial 97-78 (US Patent 6316493 B1, 2001) in male and female rats after single oral and intravenous administration. The pharmacokinetic profile of 97-78 was investigated in the form of its completely converted metabolite 97-63 after dose administration. Quantification of metabolite 97-63 in rat plasma was achieved using a simple and rapid LC-MS/MS method. The LC-MS/MS method has been validated in terms of accuracy, precision, sensitivity and recovery for metabolite 97-63 in rat plasma. The intra- and interday accuracy (% bias) and precision (% RSD) values of the assay were less than 10% for metabolite 97-63. The chromatographic run time was 4.0 min and the weighted (1/x2) calibration curves were linear over the range 1.56-200 ng/ml. This method was successfully applied for analysis of pharmacokinetic study samples. Maximum plasma concentrations of 97-63 at 47 mg/kg oral administration in male and female rats were 1986.6 ng/ml and 4086.7 ng/ml at time (Tmax) 0.92 h and 0.58 h, respectively. The area under the curve (AUC(0-infinity)), elimination half-life (t(1/2) beta) and mean residence time (MRT) were 4669.98 ng x h/ml, 2.8 h and 4.2 h in male and 11786.0 ng x h/ml, 4.52 h and 4.32 h in female rats respectively. After single oral and intravenous administration of 97-78 to male and female rats significant differences were observed in pharmacokinetic parameters (AUC and t (1/2) beta) for metabolite 97-63.
authors.affiliation: Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow, India.
authors.forename: Rajendra Pratap
authors.initials: RP
authors.lastname: Singh
authors.forename: S
authors.initials: S
authors.lastname: Sabarinath
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.forename: Ram Chandra
authors.initials: RC
authors.lastname: Gupta
authors.forename: Shio Kumar
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012727:Sex Characteristics; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: C557687:97-78 compound; D000962:Antimalarials; D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D013141:Spiro Compounds