Quantitation of SAR97276 in mouse tissues by rapid resolution liquid chromatography-mass spectrometry.
1,12-Bis[5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium]dodecane dibromide (SAR97276, T3) is a new antimalarial drug, which is currently being evaluated in clinical trials for severe malaria. Drug accumulation inside the parasite and a dual mechanism of action are a major strength of this compound, as it could help delay the development of resistance. The purpose of this article was to develop a rapid resolution LC-MS method for quantifying SAR97276 in mouse tissues. The LC system consisted of Zorbax Eclipse XDB C8 (1.8 microm, 50 x 4.6 mm, 60 degrees C) column. Elution with a gradient mobile phase consisting of ACN-trimethylamine-formate buffer (pH 3) at a flow rate of 1 mL/min yielded sharp, utmost-resolved peaks within 2 min. Tissue samples were powdered under liquid nitrogen. After protein precipitation with citric acid, SPE using WCX cartridges was used for sample preparation. There was no influence of the matrix on the detection of either SAR97276 or the IS. Assay precision was <13% and accuracy was 90-107%. The lower LOQs were 3.3 microg/kg in brain and 33 microg/kg in liver and heart. This newly developed method was used to study the tissue distribution of SAR97276 in mouse as part of the ongoing development of SAR97276.
Margout
Delphine
D
EA 4215, Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, Montpellier I University, Montpellier, France.
Wein
Sharon
S
Gandon
Hermine
H
Gattacceca
Florence
F
Vial
Henri J
HJ
Bressolle
Françoise M M
FM
D000818:Animals; D001921:Brain; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D005260:Female; D006321:Heart; D008099:Liver / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D015394:Molecular Structure; D013844:Thiazoles / Q000032:analysis* / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
C499114:1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane; D013844:Thiazoles