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Liquid chromatography–tandem mass spectrometry method for determining tolvaptan and its nine metabolites in rat serum: application to a pharmacokinetic study

Author:
Furukawa, Masayuki, Miyata, Kenichi, Kawasome, Chie, Himeda, Yoshiko, Takeuchi, Kenji, Koga, Toshihisa, Hirao, Yukihiro, Umehara, Ken
Source:
Archives of pharmacal research 2014 v.37 no.12 pp. 1578-1587
ISSN:
0253-6269
Subject:
antagonists, blood serum, females, ionization, liquid chromatography, males, metabolites, monitoring, pharmacokinetics, rats, solid phase extraction, tandem mass spectrometry, vasopressin
Abstract:
Tolvaptan is a competitive vasopressin V₂-receptor antagonist that inhibits water reabsorption in the renal collecting ducts. A selective and sensitive liquid chromatography–tandem mass spectrometry method for determining tolvaptan and its nine metabolites in rat serum was developed and validated. An analogue of tolvaptan was used as an internal standard. Sample preparation involved protein precipitation following solid-phase extraction. Chromatographic separation was performed on a C₁₈reversed-phase column with a linear gradient elution. The flow rate was 0.25 mL/min, and total run time was 30 min. The analytes were detected by tandem mass spectrometry using an electrospray ionization interface in positive ion mode and multiple reaction monitoring. The calibration curve showed linearity over the concentration range from 5 to 1,000 ng/mL for each analyte. The lower limit of quantification using 0.1 mL of rat serum was 5 ng/mL for each analyte. Precision did not exceed 5.7 %, and accuracy as relative error were within ± 7.5 % for all analytes. The validated method was successfully applied to evaluate the pharmacokinetics of oral tolvaptan in rats, indicating the systemic exposure to tolvaptan in females eight times larger than that in males.
Agid:
1192722