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  • Title: LC-MS/MS assay for the determination of a novel anti-fibrotic candidate mefunidone in monkey plasma and its application to a pharmacokinetics study.
    Author: Han X, Wen Z, Fan Z, Ma Y, Wang L, Cheng Z.
    Journal: Drug Test Anal; 2019 Jul; 11(7):1057-1064. PubMed ID: 30869197.
    Abstract:
    Mefunidone (MFD) is a promising anti-fibrotic candidate molecule with greater anti-fibrotic activity than pirfenidone (PFD). However, there has been no report on the methodology used for the quantification of MFD or on any investigation of its pharmacokinetics. In this study, an efficient and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to assay MFD in monkey plasma. This assay method was validated and applied to a pharmacokinetics study in monkeys. The lower limit of quantification of this assay was 0.1 μg·mL-1 , and the linear calibration curve was acquired with R2  > 0.99 between 0.1 and 60 μg·mL-1 . The intra-day and inter-day precision were evaluated with coefficient of variations of 1.5%-5.8%, whereas the mean accuracy ranged from 91.7% to 106.9%. A negligible matrix effect and good recovery were obtained using this assay, with average extraction recoveries of MFD and the internal standard (IS) in the range of 85.5%-124.8% and 84.1%-94.0%, respectively. The precision of the absolute matrix effect of MFD and the IS was 1.2-3.0% and 1.2-7.3%, respectively. The samples were stable under all experimental conditions. Linear pharmacokinetics were observed for MFD in monkeys, where the exposures of MFD increased proportionally with increasing MFD doses at the range of 10-90 mg·kg-1 . Moderate elimination of MFD from the body was observed, with t1/2 of 5-7 h, and the elimination rate of MFD was stable during multiple dosing. In conclusion, this method provides an reliable analytical approach for quantification of MFD in plasma and was successfully applied to a pharmacokinetics study in monkeys.
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