title: Rapid resolution liquid chromatography-mass spectrometry determination of SAR97276 in monkey matrices. Pharmacokinetics in rhesus monkey infected by Plasmodium cynomolgi.
abstract: Since several years, we developed a new class of antimalarial drugs targeting the phospholipid metabolism of the Plasmodium falciparum malaria parasite. The bis-thiazolium compound, SAR97276, is the lead compound and is now in clinical development. In this paper, we applied the fast rapid resolution liquid chromatography-mass spectrometry technique to the analysis of SAR97276 in monkey matrices. The sample pre-treatment procedure involved an acidic precipitation of proteins followed by solid-phase extraction. The monocationic compound, T2, was used as internal standard. A good separation was achieved on a Zorbax eclipse XDB C8 column (1.8 microm, 50 mm x 4.6mm) with a mobile phase consisting of acetonitrile-trimethylamine-formate buffer (pH 3) gradient elution. The total run time was 8 min. Inter-assay precisions were <10% in plasma, and <or=12% in blood. Accuracies were 96.6-98.1% (plasma) and 94.5-103% (blood). Mean extraction efficiencies were >85% in plasma, and >75% in blood. The lower limits of quantitation were 3.3 microg/l in plasma and 3.3 microg/kg in blood. No matrix effect was observed. This newly developed method is sensitive, selective, reproducible, and stability indicating. It was used to analyse samples taken during a pharmacokinetic/pharmacodynamic study carried out in infected Rhesus monkey by Plasmodium cynomolgi as part of the ongoing development of SAR97276.
authors.affiliation: EA 4215, Pharmacokinetic Laboratory, Faculty of Pharmacy, 15 Avenue Ch. Flahault, Montpellier I University, 34093 Montpellier Cedex 5, France.
authors.forename: D
authors.initials: D
authors.lastname: Margout
authors.forename: N
authors.initials: N
authors.lastname: Bontemps
authors.forename: C H M
authors.initials: CH
authors.lastname: Kocken
authors.forename: H J
authors.initials: HJ
authors.lastname: Vial
authors.forename: F M M
authors.initials: FM
authors.lastname: Bressolle
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D002021:Buffers; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005615:Freezing; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D008253:Macaca mulatta; D008288:Malaria / Q000097:blood*; D013058:Mass Spectrometry / Q000379:methods*; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D016789:Plasmodium cynomolgi; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D052616:Solid Phase Extraction / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
chemical_list: C499114:1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane; D000962:Antimalarials; D002021:Buffers; D013844:Thiazoles