title: Simultaneous determination of OZ277, a synthetic 1,2,4-trioxolane antimalarial, and its polar metabolites in rat plasma using hydrophilic interaction chromatography.
abstract: OZ277 is a synthetic 1,2,4-trioxolane antimalarial currently being evaluated in clinical trails. Biotransformation of OZ277 in rats results in the generation of metabolites with large differences in polarity which complicates the development of a method for the simultaneous analysis of all species. A simple, sensitive and selective hydrophilic interaction liquid chromatography-mass spectroscopy (HILIC/MS) method for simultaneous determination of OZ277 and its major metabolites in rat plasma was developed and validated. The method involves protein precipitation with acetonitrile followed by separation on a Waters Atlantis HILIC Silica column using gradient elution. The analytes were monitored using a positive electrospray ionization interface in selected ion monitoring mode. The calibration range for all of the analytes was 5-10,000ng/mL and the lower limit of quantitation was 5ng/mL using a 50microL rat plasma sample. The inter- and intra-day accuracy and precision was within 12%. The recovery of all analytes from rat plasma over a wide concentration range was 90% or greater. The method has been successfully used for quantifying OZ277 and its metabolites in plasma following intravenous administration to rats.
authors: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors: Ravi K
authors: RK
authors: Bhamidipati
authors: Julia
authors: J
authors: Morizzi
authors: Francis C K
authors: FC
authors: Chiu
authors: David M
authors: DM
authors: Shackleford
authors: Susan A
authors: SA
authors: Charman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods*; D004355:Drug Stability; D006573:Heterocyclic Compounds, 1-Ring / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D010545:Peroxides / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013141:Spiro Compounds / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000962:Antimalarials; D006573:Heterocyclic Compounds, 1-Ring; D010545:Peroxides; D013141:Spiro Compounds; C489136:arterolane