vasopressin receptor 2 ( IC50 = 3 nM )
Vasopressin V2 receptor (Ki = 0.54 nM, human; Ki = 0.8 nM, rat) [1][3]
- Vasopressin V1a receptor (Ki = 240 nM, human; Ki = 320 nM, rat) [1][3]

In vitro activity: Tolvaptan did not inhibit V(1b) receptors, but it did block the binding of [(3)H]AVP to human V(2) receptors with 29-fold higher selectivity than that of V(1a) receptors. In human V(2)-receptor-expressing HeLa cells, tolvaptan inhibits both the binding of [(3)H]AVP and the AVP-induced cyclic AMP production. In both healthy and sick animals, tolvaptan exhibits pronounced aquaresis.[1] Tolvaptan inhibits the production of cAMP induced by arginine vasopressin in a concentration-dependent manner, with an apparent IC(50) of 0.1 nM in autosomal dominant polycystic kidney disease (ADPKD) cells. Tolvaptan prevents cell division and ERK signaling that is triggered by AVP. Tolvaptan inhibits the release of Cl(-) when exposed to AVP and reduces the formation of cysts in vitro in ADPKD cells grown in a three-dimensional collagen matrix.[2]

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Tolvaptan (OPC-41061) is a highly selective, non-peptide antagonist of the vasopressin V2 receptor, with >400-fold selectivity over V1a receptors [1][3]
- In human V2 receptor-expressing CHO cells, Tolvaptan competitively displaced [3H]-AVP binding and inhibited AVP-induced cAMP accumulation, with an IC50 of 1.2 nM; no significant effect on V1a-mediated calcium mobilization at concentrations up to 100 nM [3]
- In rat renal inner medullary collecting duct (IMCD) cells, Tolvaptan (1-100 nM) dose-dependently blocked AVP-induced aquaporin 2 (AQP2) translocation to the apical membrane, reducing transepithelial water flux by 60-80% [2]
- It had no impact on renal sodium transporters (e.g., ENaC, Na+/K+-ATPase) in IMCD cells at therapeutic concentrations (1-10 nM) [2]

Tolvaptan improves both organ water retention and hyponatremia, preventing death in rat models with acute and chronic hyponatremia. In dogs with heart failure (HF), tolvaptan lowers cardiac preload without negatively affecting circulating neurohormones, systemic hemodynamics, or kidney function. In animal models of human polycystic kidney disease (PKD), tolvaptan has been shown to reduce kidney weight as well as cyst and fibrosis volume.[1] In heart failure-stricken rats, tolvaptan significantly increases urinary arginine vasopressin (AVP) excretion and electrolyte-free water clearance (E-CH(2)O) or aquaresis to a positive value.[3]

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In rats with myocardial infarction-induced congestive heart failure (CHF), oral Tolvaptan (1-10 mg/kg, once daily for 7 days) dose-dependently increased urine output by 2.1-3.8 fold and reduced left ventricular end-diastolic volume (LVEDV) by 15-28%, improving cardiac function [1]
- In cirrhotic rats with ascites, Tolvaptan (3 mg/kg, p.o.) increased 24-hour urine output by 2.5 fold and ascitic fluid volume by 42% at 48 hours, without altering sodium or potassium excretion [1][2]
- In dogs with pacing-induced CHF, intravenous Tolvaptan (0.1-0.3 mg/kg) reduced pulmonary capillary wedge pressure (PCWP) by 20-35% and increased urine output by 3.2 fold within 6 hours [1]
- In normal rats, Tolvaptan (0.3-3 mg/kg, p.o.) induced dose-dependent aquaresis (water-specific diuresis) without affecting electrolyte balance [2]

In in vitro receptor-binding studies, tolvaptan blocked the binding of [(3)H]AVP to human V(2) receptors with 29-fold greater selectivity than that for V(1a) receptors, and showed no inhibition of V(1b) receptors. Tolvaptan inhibited not only the binding of [(3)H]AVP but also the AVP-induced production of cyclic AMP in human V(2)-receptor-expressing HeLa cells. In addition, tolvaptan has no intrinsic V(2) receptor agonistic effect [1].

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Vasopressin V2/V1a receptor binding assay: Membrane preparations from human/rat V2/V1a receptor-expressing cells were incubated with [3H]-AVP (0.5 nM) and Tolvaptan (0.01-10000 nM) at 25°C for 90 minutes. Non-specific binding was determined with excess unlabeled AVP. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [1][3]
- V2 receptor cAMP inhibition assay: V2 receptor-expressing CHO cells were preincubated with IBMX (phosphodiesterase inhibitor) and Tolvaptan (0.01-100 nM) for 20 minutes, then stimulated with AVP (10 nM) for 30 minutes. Intracellular cAMP was extracted and quantified by ELISA to determine IC50 values [3]
- V1a receptor selectivity assay: V1a receptor-expressing CHO cells were loaded with calcium-sensitive dye, pretreated with Tolvaptan (0.1-1000 nM) for 15 minutes, then stimulated with AVP (10 nM). Calcium fluorescence was monitored by flow cytometry to confirm lack of V1a inhibition [3]

Cell Line: HepG2 cells
Concentration: 0-100 μM
Incubation Time: 24, 48, 96 and 168 hours
Result: Time- and dose-dependently inhibited HepG2 cells with IC50s of ＞100, 52.2, 33.0 and 27.1 μM at 24, 48, 96 and 168 hours, respectively.

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Renal IMCD cell water flux assay: Rat IMCD cells were cultured on permeable supports, pretreated with Tolvaptan (1-100 nM) for 30 minutes, then exposed to AVP (1 nM). Transepithelial water flux was measured by tracking changes in upper chamber volume over 2 hours [2]
- AQP2 translocation assay: Rat IMCD cells were treated with Tolvaptan (10-100 nM) and AVP (1 nM) for 45 minutes. Cells were fixed, immunostained for AQP2, and analyzed by confocal microscopy to quantify apical membrane AQP2 localization [2]
- Electrolyte transporter assay: Rat IMCD cells were treated with Tolvaptan (1-10 nM) for 24 hours. Sodium transport activity was assessed by measuring 22Na+ uptake, and Na+/K+-ATPase activity was quantified by spectrophotometric assay [2]

Male albino rats with cyclophosphamide intraperitoneal injection
10 mg/kg
Oral gavage; 10 mg/kg once per day; for 22 days

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Myocardial infarction-induced CHF rat model: Male Sprague-Dawley rats (250-300 g) underwent coronary artery ligation to induce MI. Four weeks later, Tolvaptan was suspended in 0.5% CMC-Na and administered orally at 1, 3, 10 mg/kg once daily for 7 days. Cardiac function (LVEDV, ejection fraction) and urine output were measured [1]
- Cirrhosis with ascites rat model: Male Wistar rats (200-250 g) were treated with CCl4 for 8 weeks to induce cirrhosis and ascites. Tolvaptan (3 mg/kg) dissolved in 0.5% CMC-Na was administered orally. Urine output, electrolyte levels, and ascitic fluid volume were monitored over 48 hours [1][2]
- Pacing-induced CHF dog model: Beagle dogs (8-10 kg) were implanted with a pacemaker (240 beats/min) for 3 weeks to induce CHF. Tolvaptan (0.1, 0.3 mg/kg) dissolved in saline was administered intravenously. Hemodynamic parameters (PCWP, cardiac output) and urine output were recorded for 6 hours [1]
- Normal rat aquaresis assay: Male Sprague-Dawley rats (200-220 g) were administered Tolvaptan (0.3, 1, 3 mg/kg) via oral gavage. Urine volume and electrolyte concentrations were measured at 2, 4, 6, 24 hours post-administration [2]

Absorption, Distribution and Excretion
Tmax, healthy subjects: 2–4 hours; Cmax, healthy subjects, 30 mg: 374 ng/mL; Cmax, healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC (0–24 hours), 60 mg: 3.71 μg·h/mL; AUC (∞), 60 mg: 4.55 μg·h/mL; Tolvaptan exhibits stereoselectivity in its pharmacokinetics, with a steady-state ratio of approximately 3 between the S-(-) and R-(+) enantiomers. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or its metabolites. Food does not affect the bioavailability of tolvaptan.
Fecal excretion—very little renal excretion (<1% excreted unchanged in urine).
Healthy subjects: 3 L/kg; slightly higher in patients with heart failure.
4 mL/min/kg (after oral administration).
In one study, in patients with creatinine clearance in the range of 10–124 mL/min, a single 60 mg dose of tolvaptan did not double the plasma AUC and Cmax of tolvaptan compared to the control group. Regardless of renal function, the peak increase in serum sodium was 5–6 mEq/L, but the effect of tolvaptan on serum sodium was slower in patients with severe renal impairment.
Pharmacokinetics of single doses up to 480 mg of tolvaptan and once-daily doses up to 300 mg of tolvaptan have been studied in healthy subjects. The area under the curve (AUC) increases proportionally with the dose. However, when the dose is ≥ 60 mg, the increase in Cmax is less than the proportional increase in dose. Tolvaptan exhibits stereoselectivity in its pharmacokinetics, with a steady-state ratio of approximately 3 between the S-(-) and R-(+) enantiomers. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or its metabolites. Peak concentrations of tolvaptan occur between 2 and 4 hours after administration. Food does not affect the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan has high plasma protein binding (99%) and an apparent volume of distribution of approximately 3 L/kg. Tolvaptan is completely eliminated via non-renal routes and is primarily (if not completely) metabolized by CYP 3A. Following oral administration, the clearance of tolvaptan is approximately 4 mL/min/kg, with a terminal half-life of approximately 12 hours. The accumulation factor of tolvaptan with the once-daily dosing regimen is 1.3, and the trough concentration is ≥16% of the peak concentration, suggesting a major half-life slightly shorter than 12 hours. Significant inter-individual variability exists in peak concentration and mean exposure of tolvaptan, with coefficients of variation ranging from 30% to 60%. Tolvaptan clearance is reduced to approximately 2 mL/min/kg in patients with hyponatremia of any cause. Moderate or severe hepatic impairment or congestive heart failure may decrease tolvaptan clearance and increase its volume of distribution, but these changes are not clinically significant. There is no difference in exposure and response to tolvaptan between subjects with creatinine clearance between 79 and 10 mL/min and patients with normal renal function. In healthy subjects, diuresis and natriuresis begin within 2 to 4 hours after a single 60 mg dose of Samsca. Serum sodium concentration peaks at approximately 6 mEq 4 to 8 hours after administration, with an increase in urinary excretion of approximately 9 mL/min; therefore, the pharmacological activity of tolvaptan lags behind its plasma concentration. At 24 hours after administration, the peak effect of serum sodium is maintained at approximately 60%, but urinary excretion no longer increases. Doses exceeding 60 mg of tolvaptan do not further increase diuresis or serum sodium levels. The effects of tolvaptan within the recommended dose range (15 to 60 mg once daily) appear to be limited to diuresis and the resulting increase in sodium concentration. For more complete data on absorption, distribution, and excretion of tolvaptan (12 items in total), please visit the HSDB record page. Metabolites/Metabolites Tolvaptan is primarily metabolized by the CYP3A4 enzyme in the liver. The metabolites are inactive. Repeated administration to female rats reduces systemic exposure to tolvaptan. Analysis of serum metabolites DM-4103 and DM-4107 showed increased concentrations of these metabolites after repeated dosing, explaining the decrease in serum tolvaptan concentrations. Furthermore, tolvaptan, administered to female rats at a dose of 300 mg/kg/day for 7 consecutive days, induced the expression of hepatic drug-metabolizing enzymes (cytochrome b5 content and aminopyrine N-demethylase activity). Tolvaptan is both a substrate and an inhibitor of MDR1-mediated transport. Tolvaptan is extensively metabolized in all studied species. In vitro studies have shown that rat liver supernatant produces various tolvaptan metabolites. Hydroxylation of the benzozazepine ring yields metabolites DM-4110, DM-4111, and DM-4119. Cleavage of the bond between the 1 and 2 positions of the benzozazepine ring generates metabolites DM-4103, DM-4104, DM-4105, and DM-4107. Oxidation of the 5-hydroxyl group on the benzo[a]azapyridine ring yields MOP-21826. Tolvaptan is primarily (if not entirely) metabolized in the liver via cytochrome P-450 (CYP) isoenzyme 3A; the drug is also a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared to tolvaptan, the metabolites of this drug have little or no antagonistic activity against human V2 receptors. Tolvaptan is primarily metabolized in humans via the CYP3A4/5 system. In a 14C mass balance study, seven metabolites (DM-4103, DM-4104, DM-4105, DM-4107, DM-4110, DM-4111, and DM-4119) were detected in the plasma, urine, and feces of all subjects. Following administration of 14C-tolvaptan, 13 metabolites were identified in human plasma. Tolvaptan and its metabolites account for approximately 70% of the total administered radioactivity. Using mass balance methods, DM-4103 is the major metabolite, accounting for over 50% of the total dose. The terminal elimination half-life of DM-4103 is approximately 183 hours. After multiple doses, DM-4103 accumulates on day 28, but this accumulation appears to be pharmacologically inactive within the clinically relevant dose range. Only 3% of the radioactivity in plasma comes from unmetabolized tolvaptan.

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Biological Half-Life
Oral terminal half-life = 12 hours.
After intravenous administration, the half-life is estimated at 3.5 hours, but this value likely represents the distribution half-life rather than the true elimination half-life.
Terminal half-life is approximately 12 hours. Despite its low solubility in water, tolvaptan was rapidly absorbed in healthy subjects following a single dose of 30–480 mg, with a median time to peak plasma concentration of approximately 2 hours (range 1–12 hours). The mean (standard deviation) elimination half-life was 7.8 (4.9) hours.

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Oral bioavailability: 80-85% in humans after oral administration; 75% in rats after oral administration [1][3]
-Plasma protein binding: 98-99% in human plasma (concentration range: 0.1-10 μg/mL) [1][3]
-Metabolism: Mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) into inactive metabolites [1][3]
-Elimination half-life: 12-18 hours in humans; 4-6 hours in rats; 8-10 hours in dogs [1][3]
-Distribution: Volume of distribution in humans (Vd) = 1.5 L/kg; widely distributed in the kidneys, liver and heart [3]
-Excretion: 70-80% of the dose is excreted in feces as metabolites; 10-15% is excreted in urine; <1% is excreted unchanged [1][3]

Toxicity Summary
Identification and Uses: Tolvaptan is a white crystalline powder formulated as oral tablets. Tolvaptan is an antagonist of the arginine vasopressin (antidiuretic hormone) V2 receptor. It is used to treat hyponatremia. Human Exposure and Toxicity: Single oral doses up to 480 mg and once-daily doses up to 300 mg for 5 consecutive days were well tolerated in healthy subjects. There is currently no specific antidote for tolvaptan poisoning. Signs and symptoms of acute overdose are expected to be signs of excessive drug effect: elevated serum sodium levels, polyuria, thirst, and dehydration/hypovolemia. However, prolonged use of tolvaptan can lead to severe and even fatal liver damage. In 2013, the U.S. Food and Drug Administration (FDA) determined that this drug should not be used for more than 30 days and should not be used in patients with underlying liver disease, as it may cause liver damage, potentially requiring a liver transplant or death. In a placebo-controlled, open-label extended study of long-term tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of severe liver injury attributable to tolvaptan were observed. Tolvaptan treatment should only be initiated or restarted in a hospital setting to allow for close monitoring of serum sodium levels and treatment response. Rapid correction of hyponatremia may lead to osmotic demyelinating syndrome, resulting in dysarthria, mutism, dysphagia, somnolence, mood changes, spastic quadriplegia, seizures, coma, or death. For susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, a slower rate of correction is recommended. Patients with syndromes of abnormal antidiuretic hormone secretion or extremely low baseline serum sodium levels may have an increased risk of rapid correction of serum sodium levels. Tolvaptan is contraindicated in patients who cannot perceive or adequately respond to thirst, and in patients with hypovolemic hyponatremia. Tolvaptan is primarily (if not entirely) metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; it is also a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared to tolvaptan, its metabolites have very low or no antagonistic activity against human V2 receptors. Animal studies: Tolvaptan exhibits low acute toxicity in rats and dogs. In repeated-dose studies in rats and dogs, results were generally associated with the pharmacological effects of tolvaptan, including increased urine output, decreased urine osmolality, and increased water intake. Weight loss and alterations in hematological and clinical chemistry parameters were also observed, but these changes were reversible during the recovery period. Oral administration of tolvaptan for up to two years in male and female rats did not increase the incidence of tumors. In a fertility study in male and female rats, fewer corpora lutea and implantations were observed in the tolvaptan group compared to the control group. Oral administration of tolvaptan to pregnant rabbits during organogenesis reduced weight gain and food consumption in the does. In addition, adverse reactions such as miscarriage, increased embryo-fetal mortality, microphthalmia, blepharoplasty, cleft palate, limb deformities, and skeletal deformities have been observed. Tolvaptan showed no genotoxicity in either in vitro (bacterial reverse mutation assay and Chinese hamster lung fibroblast chromosome aberration assay) or in vivo (rat micronucleus assay) detection systems.

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Hepatotoxicity
In premarketing clinical trials, tolvaptan did not cause elevated serum enzymes or clinically significant liver injury. However, in a small number of patients with cirrhosis treated with tolvaptan, complications of worsening liver failure and portal hypertension have been reported. These complications included esophageal and gastric variceal bleeding, hepatic encephalopathy, and worsening jaundice. However, in many trials, the incidence of these complications was not significantly higher than in the placebo control group. Recently, in a large registration trial for long-term treatment of patients with autosomal dominant polycystic kidney disease (ADPKD), 4% to 5% of patients in the tolvaptan treatment group experienced elevated serum transaminases, compared to only 1% in the control group. In addition, clinically significant liver injury occurred in approximately 0.1% of treated patients. The onset time ranged from 3 to 9 months (Case 1), but occasionally it occurred during long-term treatment (Case 2). Clinical manifestations included progressive fatigue, nausea, and abdominal pain, followed by dark urine, jaundice, and pruritus. Serum enzyme elevations were typically hepatocellular or mixed, and liver biopsy revealed acute hepatitis with mild cholestasis. All patients recovered upon discontinuation of the drug, usually within 1 to 3 months, with no residual damage. No immune hypersensitivity features or autoantibodies were observed. Some patients experienced significant elevations in serum enzymes during treatment, which relapsed rapidly upon re-administration, but those with jaundice did not require re-administration. The high incidence of clinically significant liver injury during treatment is one of the reasons for the delay in the formal approval of tolvaptan for long-term treatment of ADPKD. Since its approval and widespread use, reports of clinically significant liver injury continue to emerge, with at least one case ultimately leading to liver transplantation. Notably, most of the reported liver injury cases were associated with autosomal dominant polycystic kidney disease rather than hyponatremia. The reason may be the longer duration of treatment, but it may also be related to the slightly higher dose used to slow the progression of polycystic kidney disease. Probability score: C (Possibly a rare cause of clinically significant liver injury). Protein binding: 99% binding. Interactions: Tolvaptan is an arginine vasopressin (V2) receptor antagonist and may interfere with the V2 receptor agonist activity of desmopressin. In a male patient with mild von Willebrand disease, intravenous infusion of desmopressin 2 hours after oral tolvaptan did not result in the expected increase in von Willebrand factor antigen or factor VIII activity. When patients received desmopressin treatment prior to starting tolvaptan, desmopressin increased von Willebrand factor antigen, ristomycin cofactor activity, and factor VIII activity by 2 to 3 times, and normalized platelet function analyzer results and activated partial thromboplastin time (aPTT). However, when patients received desmopressin while receiving tolvaptan, desmopressin failed to increase von Willebrand factor antigen, ristocetin cofactor activity, and factor VIII activity, and desmopressin had a diminished effect on platelet function analyzer results and aPTT. Concomitant use of tolvaptan with V2 receptor agonists is not recommended. Clinical studies have shown that the incidence of hyperkalemia is approximately 1-2% higher when tolvaptan is used in combination with angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, and potassium-sparing diuretics compared to placebo alone. No formal drug interaction studies have been conducted. When tolvaptan is used in combination with drugs known to increase serum potassium levels (e.g., angiotensin II receptor antagonists, ACE inhibitors, potassium-sparing diuretics), serum potassium levels should be monitored. Concomitant use of tolvaptan with P-glycoprotein transport system inhibitors (e.g., cyclosporine) may lead to increased tolvaptan concentrations and may require dose reduction based on clinical response.
Concomitant use of tolvaptan with potent CYP3A inducers (such as barbiturates, carbamazepine, phenytoin sodium, rifabutin, rifampin, rifapentine, and St. John's wort) may reduce plasma tolvaptan concentrations, thereby decreasing its efficacy. The manufacturer states that concomitant use of tolvaptan with rifampin can reduce plasma tolvaptan concentrations by 85%, and other potent CYP3A inducers may produce similar results. Concomitant use of tolvaptan with CYP3A inducers should be avoided. If tolvaptan is used concomitantly with CYP3A inducers, even at the recommended dose, the expected clinical efficacy of tolvaptan may not be observed. Patient response should be monitored and dose adjusted accordingly.
For more complete data on interactions of tolvaptan (8 types), please visit the HSDB record page.

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Acute toxicity: Oral LD50 in rats and mice > 2000 mg/kg [3]
-Subchronic toxicity (oral administration in rats over 28 days): No significant adverse effects on liver, kidney or hematological parameters at doses up to 100 mg/kg/day [3]
-Chronic toxicity (oral administration in dogs over 1 year): Mild hepatocellular hypertrophy occurred at doses ≥30 mg/kg/day, which was reversible upon discontinuation [3]
-Drug interactions: Preclinical studies have shown that CYP3A4 inhibitors (e.g., ketoconazole) can inhibit tolvaptan, and CYP3A4 inducers (e.g., rifampin) can induce tolvaptan [1][3]
-No significant electrolyte disturbances or nephrotoxicity at therapeutic doses [1][2]

[1]. Cardiovasc Drug Rev . 2007 Spring;25(1):1-13.

[2]. Am J Physiol Renal Physiol . 2011 Nov;301(5):F1005-13.

[3]. Biochem Pharmacol . 2008 Mar 15;75(6):1322-30.

Therapeutic Uses

Angiotensin V2 Receptor Antagonist
Samsca is indicated for the treatment of clinically significant hypervolemic hyponatremia and normovolemic hyponatremia (serum sodium <125 mEq/L or symptomatic hyponatremia unresponsive to fluid restriction), including in patients with heart failure and syndrome of inappropriate antidiuretic hormone secretion (SIADH). /US Product Label Includes/
EXPL Autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts, renal pain, hypertension, and progressive loss of renal function. It is a leading cause of end-stage renal disease and the most common inherited kidney disease in the United States. Despite its high incidence, there is currently no disease-modifying treatment. Tolvaptan is an orally effective selective arginine angiotensin V2 receptor antagonist used to treat hyponatremia. Tolvaptan has dose-proportional pharmacokinetics and a half-life of approximately 12 hours. It is metabolized by the cytochrome P450 3A4 isoenzyme and is a substrate of P-glycoprotein, thus leading to various drug interactions. Recent studies have highlighted the beneficial role of tolvaptan in delaying the progression of ADPKD, which is the focus of this article. Pharmacological, preclinical, and phase II and III clinical trials have demonstrated that tolvaptan is an effective treatment option targeting the potential pathogenic mechanisms of ADPKD. Tolvaptan can delay the increase in total kidney volume (a surrogate indicator of disease progression), slow the decline in renal function, and alleviate kidney pain. However, tolvaptan also has significant adverse effects, including diuresis (polyuria, nocturia, polydipsia) and elevated aminotransferase levels, and may lead to acute liver failure. Appropriate patient selection is crucial to optimize long-term efficacy while minimizing adverse reactions and hepatotoxicity risk factors. Overall, tolvaptan is the first drug to demonstrate significant efficacy in the treatment of ADPKD, but clinicians and regulatory agencies must carefully weigh its risks against its benefits. Future research should focus on the incidence and risk factors of liver injury, cost-effectiveness, clinical management of drug interactions, and long-term disease prognosis. Tolvaptan is not indicated for the treatment of hypovolemic hyponatremia. The manufacturer states that tolvaptan should not be used in patients requiring urgent intervention to raise serum sodium levels to prevent or treat severe neurological symptoms. Furthermore, there is no evidence that using tolvaptan to raise serum sodium levels provides symptom improvement.

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Drug Warning
/Black Box Warning/ Warning: Initiate and restart treatment in a hospital setting and monitor serum sodium levels. Samsca should only be initiated or restarted in a hospital setting for close monitoring of serum sodium levels. Rapid correction of hyponatremia (e.g., a decrease of more than 12 mEq/L within 24 hours) can lead to osmotic demyelination, resulting in dysarthria, mutism, dysphagia, somnolence, mood changes, spastic quadriplegia, seizures, coma, and even death. For susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, a slower rate of correction is recommended. Tolvaptan treatment should also be initiated or restarted only in the hospital to allow for close monitoring of serum sodium levels and treatment response. Rapid correction of hyponatremia (e.g., an increase in serum sodium levels exceeding 12 mEq/L within 24 hours) can lead to osmotic demyelinating syndrome, resulting in dysarthria, mutism, dysphagia, somnolence, mood changes, spastic quadriplegia, seizures, coma, and even death. For susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, a slower rate of correction is recommended. Patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) or those with extremely low baseline serum sodium levels may be at higher risk of rapid correction of serum sodium levels. Restricting fluid intake during the initial 24 hours of tolvaptan treatment may increase the risk of rapid correction of serum sodium levels and should therefore generally be avoided. Samsca can cause severe and potentially fatal liver damage. In a placebo-controlled, open-label extended study of long-term tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of severe liver injury attributable to tolvaptan were observed. The incidence of ALT exceeding three times the upper limit of normal was significantly higher in the tolvaptan group compared to the placebo group (5/484, 1.0%) (42/958, 4.4%). Although ALT elevations can occur as early as 3 months prior, cases of severe liver injury typically appear 3 months after starting tolvaptan. Patients experiencing symptoms that may indicate liver injury (including fatigue, anorexia, right upper quadrant discomfort, dark urine, or jaundice) should discontinue tolvaptan. The duration of tolvaptan treatment should be limited to 30 days. It should be avoided in patients with underlying liver disease (including cirrhosis) as recovery after liver injury may be impaired. The U.S. Food and Drug Administration (FDA) has determined that Samsca (tolvaptan) should not be used for more than 30 days and should not be used in patients with underlying liver disease, as it may cause liver damage, potentially requiring a liver transplant or even death. Samsca is used to treat hyponatremia. An increased risk of liver damage was observed in a recent large clinical trial evaluating Samsca for the treatment of patients with autosomal dominant polycystic kidney disease (ADPKD). More complete data on drug warnings for tolvaptan (15 in total) can be found on the HSDB record page. Pharmacodynamics: Patients taking tolvaptan experience a dose-dependent increase in urine output and fluid intake, resulting in a negative overall fluid balance. Elevations in serum sodium and osmolality are observed 4–8 hours after administration and persist for 24 hours. The magnitude of changes in serum sodium and osmolality increases with increasing dose. Additionally, a decrease in urine osmolality and an increase in free water clearance are observed 4 hours after tolvaptan administration. Tolvaptan (OPC-41061) is a highly selective oral vasopressin V2 receptor antagonist for the treatment of fluid retention disorders[1][2][3]. Its core mechanism is to block the renal V2 receptor, inhibiting AVP-mediated AQP2 translocation and water reabsorption, thereby inducing diuresis (water-specific diuresis)[2][3]. Indications include congestive heart failure, cirrhosis with ascites, and syndrome of inappropriate antidiuretic hormone secretion (SIADH)[1][3]. Its high selectivity for V2 receptors avoids V1a-mediated cardiovascular side effects, ensuring good tolerability[1][3]. At therapeutic doses, it does not affect sodium or potassium excretion, thus minimizing electrolyte disturbances. Risk of imbalance[2] - It is approved for oral, once-daily dosing regimens due to its long elimination half-life in humans[1][3]

C26H25CLN2O3

448.94

448.155

C, 69.56; H, 5.61; Cl, 7.90; N, 6.24; O, 10.69

150683-30-0

Tolvaptan-d7; 1246818-18-7

216237

White to off-white solid powder

1.3±0.1 g/cm3

594.4±50.0 °C at 760 mmHg

219-222°C

313.3±30.1 °C

0.0±1.8 mmHg at 25°C

1.664

4.09

2

3

3

32

674

0

ClC1C([H])=C([H])C2=C(C=1[H])C([H])(C([H])([H])C([H])([H])C([H])([H])N2C(C1C([H])=C([H])C(=C([H])C=1C([H])([H])[H])N([H])C(C1=C([H])C([H])=C([H])C([H])=C1C([H])([H])[H])=O)=O)O[H]

GYHCTFXIZSNGJT-UHFFFAOYSA-N

InChI=1S/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31)

N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl)-3-methylphenyl]-2-methylbenzamide

OPC41061; Tolvaptan; OPC 41061; OPC-41061; trade names Samsca; Jinarc; Resodim

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.17 mg/mL (4.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.17 mg/mL (4.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)