Validated liquid chromatography coupled to tandem mass spectrometry method for simultaneous quantitation of tolvaptan and its five major metabolites in human plasma

Abstract

Background Tolvaptan is converted to major metabolites including three monohydroxylates (DM-4110, DM-4111 and DM-4119), an oxidate (MOP-21826) and a carboxylate (DM-4103) in humans. This study developed a simultaneous quantitative method for tolvaptan and its five major metabolites in human plasma using liquid chromatography coupled to tandem mass spectrometry. Methods Deproteinized plasma specimens using acetonitrile were separated using a 3- μm particle size octadecylsilyl column with 250 mm length and a simple linear gradient program at a flow rate of 0.3 mL/min with a total run time of 15 min. This method was applied to the determination of plasma samples collected from 20 heart failure patients treated with 3.75–15 mg tolvaptan. Results No interfering peak was found in drug-free plasma specimens. The calibration curves of tolvaptan, DM-4110, DM-4111, DM-4119, MOP-21826 and DM-4103 were linear over the concentration ranges of 3.125–1000, 0.3125–100, 1.25–400, 0.625–200, 0.125–40 and 31.25–10,000 ng/mL, respectively. Their pretreatment recovery rates and matrix factors were 94.1–113.9% and 86.9–108.0%, respectively. The intra- and inter-day accuracies and imprecisions were 91.6–106.5% and 0.9–10.9%, respectively, for all analytes. The plasma concentration ranges of tolvaptan, DM-4110, DM-4111, DM-4119, MOP-21826 and DM-4103 were 9.37–280, 1.91–16.3, 3.43–88.9, 1.43–10.4, 0.160–1.01 and 40.2–1471 ng/mL, respectively, in heart failure patients. Conclusions This validated method with acceptable analytical performance can be utilized for evaluating the pharmacokinetics of oral tolvaptan, including the determination of its major metabolites, in heart failure patients.

Simple Liquid Chromatography–Tandem Mass Spectrometry Method for Quantitation of Total and Free Aprepitant and Its Active N-Dealkylated Metabolites in Human Plasma

“…These compounds have characteristics of less matrix effect, high extraction recovery, and similar polarity to diazepam. 17,22…”

Impact of CYP3A5 genotype on tolvaptan pharmacokinetics and their relationships with endogenous markers of CYP3A activity and serum sodium level in heart failure patients

“…Plasma concentrations of tolvaptan and its metabolites including DM‐4110, DM‐4111, DM‐4119 and DM‐4103 (Otsuka Pharmaceutical Co., Ltd.) were simultaneously quantified by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) . The linearities ( r > .999) of tolvaptan, DM‐4110, DM‐4111, DM‐4119 and DM‐4103 were observed at plasma concentration ranges of 3.125‐1000, 0.3125‐100, 1.25‐400, 0.625‐200 and 31.25‐10 000 ng/mL, respectively.…”

Development of highly selective and sensitive molecularly imprinted polymer-based electrochemical sensors for tolvaptan assay in tablets and serum

“…The analysis of TOL by spectroscopic, 4–6 chromatographic, 7–18 and electrochemical techniques 19 has been reported. The methods for determination of TOL have been discussed in terms of sample handling, cost, and sensitivity.…”