LAUSR

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.