药品详细

Tolvaptan(托伐普坦)

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

托伐普坦

英文名

Tolvaptan

分子式

C₂₆H₂₅ClN₂O₃

化学名

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

分子量

Average: 448.941
Monoisotopic: 448.155370383

CAS号

150683-30-0

ATC分类

C03X 未知

药物类型

small molecule

阶段

approved

商品名

同义名

基本介绍

Tolvaptan is used to treat low blood sodium levels (hyponatremia) associated with various conditions like congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormones (SIADH). FDA approved on May 19, 2009.

生产厂家

Otsuka america pharmaceutical inc

封装厂家

参考

Synthesis Reference

Not Available

General Reference

Gheorghiade M, Teerlink JR, Mebazaa A: Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol. 2005 Sep 19;96(6A):68G-73G. Pubmed
Ambrosy A, Goldsmith SR, Gheorghiade M: Tolvaptan for the treatment of heart failure: a review of the literature. Expert Opin Pharmacother. 2011 Apr;12(6):961-76. doi: 10.1517/14656566.2011.567267. Epub 2011 Mar 15. Pubmed
Yi S, Jeon H, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS: Pharmacokinetics and pharmacodynamics of oral tolvaptan administered in 15- to 60-mg single doses to healthy Korean men. J Cardiovasc Pharmacol. 2012 Apr;59(4):315-22. doi: 10.1097/FJC.0b013e318241e89c. Pubmed
Nemerovski C, Hutchinson DJ: Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: a clinical review. Clin Ther. 2010 Jun;32(6):1015-32. doi: 10.1016/j.clinthera.2010.06.015. Pubmed
FDA label

剂型

规格

化合物类型

Type	small molecule

Classes

Not Available

Substructures

Not Available

适应症

药理

Indication	Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.
Pharmacodynamics	Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.
Mechanism of action	Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin.
Absorption	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; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan.
Volume of distribution	Healthy subjects: 3L/kg; slightly higher in heart failure patients.
Protein binding	99% bound
Metabolism	Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive.
Route of elimination	Fecal- very little renal elimination (<1% is excreted unchanged in the urine)
Half life	Terminal half life, oral dose = 12 hours.
Clearance	4 mL/min/kg (post-oral dosing).
Toxicity	The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.
Affected organisms	Humans and other mammals
Pathways	Not Available

理化性质

Properties

State

solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
water solubility	1.24e-03 g/l	ALOGPS
logP	4.14	ALOGPS
logP	5.35	ChemAxon
logS	-5.6	ALOGPS
pKa (strongest acidic)	11.76	ChemAxon
pKa (strongest basic)	-2.1	ChemAxon
physiological charge	0	ChemAxon
hydrogen acceptor count	3	ChemAxon
hydrogen donor count	2	ChemAxon
polar surface area	69.64	ChemAxon
rotatable bond count	3	ChemAxon
refractivity	129.16	ChemAxon
polarizability	48.16	ChemAxon

药物相互作用

Drug	Interaction
Barbital	Barbital is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Bicalutamide	CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of tolvaptan. This combination is contraindicated.
Carbamazepine	Carbamazepine is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Clarithromycin	Clarithromycin is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Clotrimazole	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of tolvaptan. Coadministration of a strong CYP3A4 inhibitor with tolvaptan is contraindicated.
Conivaptan	CYP3A4 Inhibitors (Strong) such as conivaptan may increase the serum concentration of Tolvaptan. Coadministration of a strong CYP3A4 inhibitor with tolvaptan is contraindicated.
Digoxin	Tolvaptan increases serum digoxin concentrations due to competitive inhibition of P-glycoprotein in the liver, intestine, and kidney. P-glycoprotein facilitates digoxin efflux thus inhibition of this protein will increase incidence of adverse effects.
Diltiazem	Diltiazem is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Erythromycin	Erythromycin is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Etravirine	Tolvaptan may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
Fluconazole	Fluconazole is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Itraconazole	Itraconazole is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Ketoconazole	Ketoconazole is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan by 82%.
Nefazodone	Nefazodone is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Phenytoin	Phenytoin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Rifabutin	Rifabutin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Rifampin	Rifampin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Ritonavir	Ritonavir is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Saquinavir	Saquinavir is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
St. John's Wort	St. John's Wort is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Verapamil	Verapamil, a moderate CYP3A4 inhibitor, may increase the serum concentration of Tolvaptan. Concomitant therapy is contraindicated.
Voriconazole	Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Tolvaptan by decreasing its metabolism. Concomitant therapy is contraindicated.

食物相互作用

Not Available

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