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药品详细

Valsartan(缬沙坦)

化学结构式图
中文名
缬沙坦
英文名
Valsartan
分子式
C24H29N5O3
化学名
(2S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)pentanamido]butanoic acid
分子量
Average: 435.5188
Monoisotopic: 435.227039819
CAS号
137862-53-4
ATC分类
C09C 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Valsartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

生产厂家
  • Novartis Corporation
  • Novartis pharmaceuticals corp
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 810-814). Berlin, Germany: Springer.
  2. Diovan. (2009). [Electronic version]. e-CPS. Retrieved December 28, 2009.
  3. Stanfield, C.L., & Germann, W.J. (2008). Principles of human physiology (3 rd ed.). San Francisco, CA: Pearson Education, Inc.
剂型
规格
化合物类型
Type small molecule
Classes
  • Biphenyltetrazoles and Derivatives
Substructures
  • Hydroxy Compounds
  • Acetates
  • Amino Ketones
  • Phenylpropenes
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Biphenyl and Derivatives
  • Biphenyltetrazoles and Derivatives
  • Carboxylic Acids and Derivatives
  • Tetrazoles
  • Phenyltetrazoles and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Cyanamides
适应症
药理
Indication May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.
Pharmacodynamics Valsartan belongs to a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Valsartan is a specific and selective type-1 angiotensin II receptor (AT1) antagonist which blocks the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: AT1 and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.
Mechanism of action Valsartan is an ARB that selectively inhibits the binding of angiotensin II to AT1, which is found in many tissues such as vascular smooth muscle and the adrenal glands. This effectively inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in a decrease in vascular resistance and blood pressure. Valsartan is selective for AT1 and has virtually no affinity for AT2. Inhibition of aldosterone secretion may inhibit sodium and water reabsorption in the kidneys while decreasing potassium excretion. The primary metabolite of valsartan, valeryl 4-hydroxy valsartan, has no pharmacological activity.
Absorption Absolute bioavailability = 23% with high variability
Volume of distribution
  • 17 L (low tissue distribution)
Protein binding 94 - 97% bound to serum proteins, primarily serum albumin
Metabolism
Valsartan is excreted largely as unchanged drug (80%) and is minimally metabolized in humans. The primary circulating metabolite, 4-OH-valsartan, is pharmacologically inactive and produced CYP2C9. 4-OH-valsartan accounts for approximately 9% of the circulating dose of valsartan. Although valsartan is metabolized by CYP2C9, CYP-mediated drug-drug interactions between valsartan and other drugs is unlikely.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Valsartan
4-Hydroxyvalsartan Details
Route of elimination 83% of absorbed valsartan is excreted in feces and 13% is excreted in urine, primarily as unchanged drug
Half life The initial phase t1/2 α is < 1 hour while the terminal phase t1/2 β is 5-9 hours.
Clearance
  • 2 L/h [IV administration]
  • 4.5 L/h [heart Failure patients receiving oral administration 40 to 160 mg twice a day]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 116-117 °C Not Available
logP 5.8 Not Available
Predicted Properties
Property Value Source
water solubility 2.34e-02 g/l ALOGPS
logP 3.68 ALOGPS
logP 5.27 ChemAxon
logS -4.3 ALOGPS
pKa (strongest acidic) 4.37 ChemAxon
pKa (strongest basic) -0.11 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 112.07 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 134.77 ChemAxon
polarizability 47.27 ChemAxon
药物相互作用
Drug Interaction
Amifostine Additive hypotensive effects may occur. At chemotherapeutic doses of Amifostine, Valsartan should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.
Amiloride Increased risk of hyperkalemia
Eltrombopag Eltrombopag may increase the therapeutic and/or toxic effects of Valsartan. Increased Valsartan serum concentrations may be caused by inhibition of hepatic uptake and decreased metabolism. Consider dose modification, alternate therapy or monitor for changes in the therapeutic and toxic effects of Valsartan if Eltrombopag is initiated, discontinued or dose changed.
Lithium Valsartan may increase serum lithium concentrations. Monitor serum lithium levels during concomitant therapy to avoid lithium toxicity.
Potassium Increased risk of hyperkalemia
Rituximab Additive hypotensive effects may occur. Increased risk of hypotension. Consider withholding Valsartan for 12 hours prior to administration of Rituximab.
Tobramycin Increased risk of nephrotoxicity
Trandolapril The angiotensin II receptor blocker, Valsartan, may increase the adverse effects of Trandolapril.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Triamterene Increased risk of hyperkalemia
食物相互作用
Not Available

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