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Development and validation of LC-MS/MS methods for the quantification of TMS-007; a member of the SMTP congeners; in rat plasma and brain: application to a preclinical pharmacokinetic study
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DOI：10.1039/D6AY00057F.png)
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Abstract
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TMS-007 is a member of the SMTP congeners for the treatment of acute ischemic stroke. To support its preclinical study; LC-MS/MS methods for the quantification of TMS-007 in rat plasma and brain were developed. The samples were prepared by protein precipitation. A UPLC HSS T3 column (2.1 mm × 50 mm; 1.8 µm) was used to achieve chromatographic separation. An acetonitrile–water mixture containing ammonium acetate was used as the mobile phase. The methods were validated with regard to selectivity; calibration curve and lower limit of quantitation; accuracy and precision; matrix effect; extraction recovery; carryover; dilution integrity; and stability. The calibration ranges of TMS-007 in rat plasma and brain homogenate were 10.0–10 000 ng mL−1. There was no endogenous or cross interference in the biological matrices. Across these matrices; the intra- and inter-batch coefficients of variation and accuracy deviations for all QC samples met the acceptance criteria. The inter-batch coefficients of variation of the QC samples were ≤11.7% for plasma and ≤15.0% for brain. The inter-batch accuracy ranged from 97.8% to 104.1% for plasma and 97.1% to 102.3% for brain. No significant matrix effect was observed from the matrices (from 102.9% to 111.0% for plasma and from 114.3% to 118.9% for brain). The extraction recoveries of the methods at different concentrations were consistent and reproducible. For plasma; the coefficients of variation were ≤9.9%; and for brain; the coefficients of variation were ≤4.6%. The analyte was stable in different matrices under various storage conditions (room temperature for 8 h; 4 °C in the autosampler for 3 days; 3 freeze–thaw cycles and 7 days at −70 °C). The methods were successfully applied to a preclinical study in a transient middle cerebral artery occlusion rat model after single dose administration. The pharmacokinetic results of the study drug laid a foundation for its further development.
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