%0 Journal Article
%T Validated liquid chromatography coupled to tandem mass spectrometry method for simultaneous quantitation of tolvaptan and its five major metabolites in human plasma
%A Junichi Kawakami
%A Kohei Hoshikawa
%A Masao Saotome
%A Takafumi Naito
%A Yuichiro Maekawa
%J Annals of Clinical Biochemistry
%@ 1758-1001
%D 2019
%R 10.1177/0004563219827045
%X 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. Deproteinized plasma specimens using acetonitrile were separated using a 3-米m particle size octadecylsilyl column with 250ˋmm length and a simple linear gradient program at a flow rate of 0.3ˋmL/min with a total run time of 15ˋmin. This method was applied to the determination of plasma samples collected from 20 heart failure patients treated with 3.75每15 mg tolvaptan. 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每1000, 0.3125每100, 1.25每400, 0.625每200, 0.125每40 and 31.25每10,000ˋng/mL, respectively. Their pretreatment recovery rates and matrix factors were 94.1每113.9% and 86.9每108.0%, respectively. The intra- and inter-day accuracies and imprecisions were 91.6每106.5% and 0.9每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每280, 1.91每16.3, 3.43每88.9, 1.43每10.4, 0.160每1.01 and 40.2每1471ˋng/mL, respectively, in heart failure patients. 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
%K Tolvaptan
%K liquid chromatography coupled to tandem mass spectrometry
%K metabolites
%K human plasma
%K method validation
%U https://journals.sagepub.com/doi/full/10.1177/0004563219827045