Determination of TA-0201, a novel orally active non-peptide endothelin antagonist, in rat plasma and tissues by a liquid chromatography--electrospray ionization--tandem mass spectrometry system

N-[6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-5-(4-methylphenyl)-4-pyrimid inyl]-4-(2-hydroxy-1, 1-dimethylethyl) benzenesulfonamide sodium salt (TA-0201) is a novel orally active non-peptide antagonist for endothelin (ET) receptors. A sensitive and simultaneous determination method of TA-0201 and its major metabolites by liquid chromatography tandem mass spectrometry (LC--MS/MS) in a selected reaction monitoring mode using [2H6]TA-0201 as the internal standard was developed, and the plasma and tissue concentrations of TA-0201 and its major metabolites were determined in a pharmacokinetic study. The lower limit of determination of plasma TA-0201 concentrations by this method was 0.1 ng/0.5 ml, and the between- and within-run accuracy and precision were both less than 5.1%, in the calibration curve range of 0.1-50 ng/0.5 ml. This method was applied to determine the concentrations of TA-0201 and its metabolites in plasma and various target tissues, i.e. the heart, lung and kidney, after oral administration of TA-0201 (0.1 mg/kg(-1)) to male rats. TA-0201 and its major metabolite of a carboxylic acid form were detected in plasma and all the tissues 24 h after administration, their tissue concentrations being higher than those in plasma and still detectable at 72 h. Thus, this method could successfully be applied to study pharmacokinetic properties of TA-0201 in rats.