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.
Ohashi
N
N
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co, Ltd, Saitama, Japan.
Nakamura
S
S
Yoshikawa
M
M
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002138:Calibration / Q000592:standards; D002853:Chromatography, Liquid / Q000379:methods; D016232:Endothelins / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D016232:Endothelins; D011743:Pyrimidines; D013449:Sulfonamides; C113972:T 0201