A rapid and sensitive LC–MS/MS-ESI method for the determination of tolvaptan and its two main metabolites in human plasma

Jiang, Juanjuan; Tian, Lei; Huang, Ye; Yan, Yan; Li, Yishi

doi:10.1016/j.jchromb.2016.03.032

Cited by 9 publications

(16 citation statements)

References 13 publications

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“…TVP is primarily metabolized by cytochrome P450 3A4 (CYP3A4) (Shoaf et al, 2011); CYP3A5, CYP2D6, uridine 5'-diphosphoglucuronosyltransferase 2B7 (UGT2B7), and UGT2B17 also contribute to TVP metabolite formation (Mazzarino et al, 2017). Numerous TVP metabolites have been identified, but most studies focus on the two major metabolites, DM-4103 and DM-4107 (Jiang et al, 2016;Lu et al, 2016). In humans, the main circulating metabolite is DM-4103, while a substantial portion of TVP is excreted in urine and feces as DM-4107 (Sorbera et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

et al. 2018

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Tolvaptan, a vasopressin V 2 -receptor antagonist, has demonstrated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) rat (n = 5), and compared with wild-type (WT) Sprague-Dawley rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean 6 S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% 6 24.72% vs. 43.40% 6 18.11% in liver, 20.10% 6 9.15% vs. 21.17% 6 12.51% in outflow perfusate, and 0.08% 6 0.01% vs. 0.39% 6 0.32% in bile. DM-4103 recovery (mean 6 S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% 6 <0.01% vs. 0.02% 6 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% 6 0.57% vs. 0.43% 6 0.29%; P = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentrations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.

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Section: Introductionmentioning

confidence: 99%

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

et al. 2018

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“…Calibration standard solutions were prepared by adding 50 μL blank rat plasma into 25 μL evaporated working standard solutions of PU‐48 and IS to achieve final concentrations of PU‐48 of 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, 50, 100, 200, 500 and 1000 ng/mL, and IS concentration of 500 ng/mL. Quality control (QC) working solutions were prepared in the same way using the low, medium and high concentrations of 0.2, 10 and 500 ng/mL, respectively (Jiang, Tian, Huang, Yan, & Li, ; Kobuchi, Matsuno, Fukuda, Ito, & Sakaeda, ). All stock solutions were stored at 4°C until used.…”

Section: Methodsmentioning

confidence: 99%

Development and validation of an LC‐MS/MS method for the determination of a novel thienoquinolin urea transporter inhibitor PU‐48 in rat plasma and its application to a pharmacokinetic study

Zhang

Wang

Liu

et al. 2017

Biomedical Chromatography

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A specific, sensitive and stable high-performance liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative determination of methyl 3-amino-6-methoxythieno [2,3-b]quinoline-2-carboxylate (PU-48), a novel diuretic thienoquinolin urea transporter inhibitor in rat plasma. In this method, the chromatographic separation of PU-48 was achieved with a reversed-phase C column (100 × 2.1 mm, 3 μm) at 35°C. The mobile phase consisted of acetonitrile and water with 0.05% formic acid added with a gradient elution at flow rate of 0.3 mL/min. Samples were detected with the triple-quadrupole tandem mass spectrometer with multiple reaction monitoring mode via electrospray ionization source in positive mode. The retention time were 6.2 min for PU-48 and 7.2 min for megestrol acetate (internal standard, IS). The monitored ion transitions were mass-to-charge ratio (m/z) 289.1 → 229.2 for PU-48 and m/z 385.3 → 267.1 for the internal standard. The calibration curve for PU-48 was linear over the concentration range of 0.1-1000 ng/mL (r > 0.99), and the lower limit of quantitation was 0.1 ng/mL. The precision, accuracy and stability of the method were validated adequately. The developed and validated method was successfully applied to the pharmacokinetic study of PU-48 in rats.

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“…10 DM-4103 exists in human plasma at the highest concentration among the tolvaptan metabolites. 11 DM-4103, with no diuretic effect, recently has been reported to potentially cause hepatic disorders through an inhibition of hepatic transporters and bile acid transporters. 12–15 Few studies on the pharmacokinetic characteristics of tolvaptan metabolites in humans have been published.…”

Section: Introductionmentioning

confidence: 99%

“…12–15 Few studies on the pharmacokinetic characteristics of tolvaptan metabolites in humans have been published. 11…”

Section: Introductionmentioning

confidence: 99%

“…A few methods using a liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) have been developed for determination of tolvaptan in human plasma. 11,16,17 However, tolvaptan metabolites in human plasma have been only rarely measured to date. 11 They reported simultaneous quantitation method of tolvaptan and two carboxylates including DM-4103 using samples taken from volunteers who received tolvaptan.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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A rapid and sensitive LC–MS/MS-ESI method for the determination of tolvaptan and its two main metabolites in human plasma

Cited by 9 publications

References 13 publications

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

Development and validation of an LC‐MS/MS method for the determination of a novel thienoquinolin urea transporter inhibitor PU‐48 in rat plasma and its application to a pharmacokinetic study

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

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