Simultaneous determination of fimasartan, a novel antihypertensive agent, and its active metabolite in rat plasma by liquid chromatography-tandem mass spectrometry.

Fimasartan, 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H tetrazol -5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (BR-A-657), is a novel angiotensin II receptor blocker exhibiting potent and selective AT1 receptor blocking activity. This study reports the liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of fimasartan and its active metabolite, BR-A-557, in rat plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification, accuracy, precision and stability. The multiple reaction monitoring was based on the transition of m/z 502.1 → 207.1 for fimasartan, 486.2 → 207.1 for BR-A-557 and 526.1 → 207.1 for BR-A-563 (internal standard). The assay utilized a simple precipitation procedure with acetonitrile and isocratic elution. The LLOQ was 0.2 ng/mL for fimasartan and BR-A-557 using 50 μL plasma samples. The assay was linear over a concentration range from 0.2 to 500 ng/mL for fimasartan and BR-A-557, with correlation coefficients >0.9995. The intra- and inter-day assay accuracies were 93.6-108.0 and 90.8-101.4% for fimasartan and 102.2-107.1 and 99.6-103.3% for BR-A-557, respectively. The intra- and inter-day precision were 2.4-4.4 and 3.0-13.4% for fimasartan and 3.1-5.2 and 2.8-9.8% for BR-A-557, respectively. The developed assay may be used to study the metabolism and mechanistic pharmacokinetics of fimasartan in future studies.