| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
