Bioanalytical method development and validation of novel antithrombotic agent S002‐333 by LC‐MS/MS and its application to pharmacokinetic studies

Abstract

A rapid, sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using an electrospray ionization (ECI) source for the quantification of novel anti-thrombotic agent S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-β-carboxylic acid amide] in rabbit plasma was developed and validated. The extraction from plasma was carried out by simple protein precipitation extraction method. The chromatographic separation was performed on an Ultramex Cyno, (150 x 4.6 mm, 5 µm) with a guard column, using acetonitrile-water (75:25,v/v) with flow rate of 0.6 mL/min as the mobile phase. The tandem mass spectrometer was tuned in the multiple reaction monitoring mode to monitor the m/z transitions 386.4/215.4 for S002-333 and m/z 393.4/171 for the internal standard dexamethasone, using positive ion mode. The MS/MS response was linear over the concentration range from 1.56 to 200 ng/mL, with a lower limit of detection of 0.78 ng/mL. The accuracy and precision of the method were within the acceptable limit of ±20% at the lower limit of quantitation and ±15% at other concentrations and showed no significant matrix effect. The validated method can be used in most or all stages of the screening and optimizing process for future method validation of pharmacokinetic studies.

Development and validation of a highly sensitive LC‐MS/MS method for the determination of dexamethasone in nude mice plasma and its application to a pharmacokinetic study

“…The MS/MS parameters were optimized using the Analyst software ‘Quantitative Optimization wizard’ to achieve maximum responses of dexamethasone and IS with reasonable values of parameters. The optimized precursor‐to‐product ion transitions monitored for DEX were m / z 393.0/147.1 while testosterone (IS) was monitored at m / z 289.5/97.3, which corresponded to the previous reports (Bhatta et al ., ; Yang et al ., ).…”

Improved oral bioavailability of novel antithrombotic S002-333 via chitosan coated liposomes: a pharmacokinetic assessment

“…3,4 The use of antiplatelet agents; aspirin, ticlopidine, and clopidogrel do not work in acute conditions and require extended periods of strictly supervised therapy mainly because of the high risk of bleeding. [7][8][9][10][11] The S002-333 is practically insoluble in water and hexane, where as it is most soluble in acetone, acetonitrile and chloroform (>10 mg mL À1 ). 1).…”

“…11 The antithrombotic agent, S002-333 suffers from poor water solubility, thus presenting major hurdles in the dissolution leading to poor bioavailability. A collagen mediated platelet activation (aggregation and adhesion) and release reaction is reduced by S002-333, which results in reduction in human platelet aggregation.…”

“…1). [7][8][9][10][11] The S002-333 is practically insoluble in water and hexane, where as it is most soluble in acetone, acetonitrile and chloroform (>10 mg mL À1 ). The partition coefficient of S002-333 was determined between octanol and water (buffer pH ¼ 7.4) and the information indicates that the compound under investigation is lipophilic in nature.…”

Simultaneous estimation of 16α‐hydroxycleroda‐3,13(14) Z‐dien‐15,16‐olide from Polyalthia longifolia and its metabolite in hamster plasma: application to pharmacokinetic study

“…This method was applied to determine the concentration of K‐09 and metabolite K‐9T in plasma after oral administration to a male hamster at a dose of 25 mg/kg. LC‐MS/MS is currently considered the method of choice for supporting preclinical and clinical pharmacokinetic studies (Bhatta et al , ). In the drug discovery and development process, identification of a new compound with potent biological activity is an important step, whereas ADME (absorption, distribution, metabolism and excretion) is a critical factor in determining the success of a new active compound as a suitable therapeutic agent.…”