title: Determination of a neuroprotective agent (S)-(+)-BMS-204352 in human, rat and dog plasma by enantioselective liquid chromatography-tandem mass spectrometry.
abstract: A sensitive liquid chromatography-electrospray ionization tandem mass spectrometry method (LC/ESI/MS/MS) for the enantioselective determination of (S)-(+)-BMS-204352, a potent and specific maxi-K channel opener, in human, rat and dog plasma was developed. (S)-(+)-BMS-204352, its enantiomer (R)-(--)-BMS-204353 and the internal standard (13C-deuterated racemate of (S)-(+)-BMS-204352) were extracted from plasma using toluene. Chromatographic separation for the enantiomers was achieved on a Chiralcel OD-H analytical column with a run time of 8 min. An aqueous mobile phase modifier was added post column to enhance the mass spectrometer sensitivity. ESI mass spectra were acquired in the negative mode with selected reaction monitoring. The limit of quantitation (LLOQ) is 0.10 ng/mL for human plasma assay. Samples from a clinical study and two animal studies were processed using these procedures. Based on the in vivo data, lack of inversion of (S)-(+)-BMS-204352 to (R)-(--)-BMS-204353 was demonstrated in human, rat and dog after administration of the drug. A sensitive non-enantioselective LC/ESI/MS/MS assay has also been developed for (S)-(+)-BMS-204352 which uses a similar extraction procedure with a C18 column with a limit of quantitation at 0.05 ng/mL. Human study samples were analyzed by both methods and the correlation coefficient between both sets of data is greater than 0.99.
authors.affiliation: Drug Disposition and Bioanalytical Science Department, Pharmaceutical Research Institute, Bristol-Myers Squibb One Squibb Drive, New Brunswick, NJ 08903, USA. jianing.zeng@bms.com
authors.forename: Jianing
authors.initials: J
authors.lastname: Zeng
authors.forename: Holly
authors.initials: H
authors.lastname: Palme
authors.forename: Nuggehally
authors.initials: N
authors.lastname: Srinivas
authors.forename: Mark
authors.initials: M
authors.lastname: Arnold
mesh_terms: D000818:Animals; D002138:Calibration; D004285:Dogs; D006801:Humans; D007211:Indoles / Q000097:blood*; D013058:Mass Spectrometry / Q000379:methods*; D018696:Neuroprotective Agents / Q000097:blood*; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013237:Stereoisomerism
chemical_list: C424388:BMS204352; D007211:Indoles; D018696:Neuroprotective Agents