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药品详细

Losartan (洛沙坦 )

化学结构式图
中文名
洛沙坦
英文名
Losartan
分子式
Not Available
化学名
[2-butyl-4-chloro-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-imidazol-5-yl]methanol
分子量
Average: 422.911
Monoisotopic: 422.162187095
CAS号
114798-26-4
ATC分类
C09C 未知
药物类型
small molecule
阶段
商品名
Cozaar (Merck & Co.);Hyzaar;Lacidipine;Lortaan;
同义名
DUP 89;Losartan Potassium;
基本介绍

An antagonist of angiotensin type 1 receptor leading to antihypertensive activity by blocking the effects of angiotensin II which include vasoconstriction and aldosterone-secretion effects. [PubChem]

生产厂家
  • Merck & Co., Inc.
  • Merck research laboratories div merck co inc
  • Teva pharmaceuticals usa inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):995-1003. Pubmed
  2. Guo ZX, Qiu MC: [Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat] Zhonghua Nei Ke Za Zhi. 2003 Jun;42(6):403-8. Pubmed
  3. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-21. Pubmed
剂型
Form Route Strength
Tablet, film coated Oral 100 mg
Tablet, film coated Oral 25 mg
Tablet, film coated Oral 50 mg
规格
Unit description Cost Unit
Losartan Potassium 90 50 mg tablet Bottle 211.78 USD bottle
Losartan Potassium-HCTZ 30 50-12.5 mg tablet Bottle 78.05 USD bottle
Hyzaar 100-25 mg tablet 3.91 USD tablet
Hyzaar 100-12.5 mg tablet 3.87 USD tablet
Hyzaar 100-12.5 tablet 3.61 USD tablet
Hyzaar 100-25 tablet 3.61 USD tablet
Losartan Potassium-HCTZ 100-12.5 mg tablet 3.54 USD tablet
Losartan Potassium-HCTZ 100-25 mg tablet 3.54 USD tablet
Cozaar 100 mg tablet 3.41 USD tablet
Losartan potassium 100 mg tablet 3.14 USD tablet
Hyzaar 50-12.5 mg tablet 2.97 USD tablet
Hyzaar 50-12.5 tablet 2.65 USD tablet
Cozaar 50 mg tablet 2.5 USD tablet
Losartan potassium 50 mg tablet 2.26 USD tablet
Cozaar 25 mg tablet 1.92 USD tablet
Losartan potassium 25 mg tablet 1.72 USD tablet
Cozaar 100 mg Tablet 1.31 USD tablet
Cozaar 25 mg Tablet 1.31 USD tablet
Cozaar 50 mg Tablet 1.31 USD tablet
化合物类型
Type small molecule
Classes
  • Biphenyltetrazoles and Derivatives
Substructures
  • Hydroxy Compounds
  • Phenylpropenes
  • Benzene and Derivatives
  • Biphenyl and Derivatives
  • Aryl Halides
  • Biphenyltetrazoles and Derivatives
  • Alcohols and Polyols
  • Tetrazoles
  • Imidazoles
  • Phenyltetrazoles and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
  • Cyanamides
适应症
ANTIHYPERTENSIVES 降血压;
药理
Indication For the treatment of hypertension.
Pharmacodynamics Losartan is the first of a class of antihypertensive agents called angiotensin II (AG II) receptor antagonists. It is, along with its longer acting active metabolite (E-3174), a specific and selective AT1 receptor antagonist. Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland).
Mechanism of action Losartan and its longer acting active metabolite (E-3174) interfere with the binding of angiotensin II to the angiotensin II AT1-receptor by, themselves, binding reversibly to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Neither Losartan or its metabolite inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels.
Absorption Well absorbed, the systemic bioavailability of losartan is approximately 33%
Volume of distribution
  • 34 L [losartan]
  • 12 L [active metabolite]
Protein binding 99.7%, primarily to albumin
Metabolism

Hepatic. Losartan is metabolized to a 5-carboxylic acid derivative (E-3174) via an aldehyde intermediate (E-3179) primarily by cytochrome P450 (CYP) 2C9 and CYP3A4. E-3174 is an active metabolite with 10- to 40-fold higher potency than its parent compound, losartan. Approxiamtely 14% of losartan is converted to E-3174; however, the AUC of E-3174 was found to be 4- to 8-fold higher than losartan and E-3174 is considered the main contributor to the pharmacologic effects of this medication.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 E-3179
Cytochrome P450 2C9 E-3179
Cytochrome P450 2C9 E-3174 oxidation 0 0
UDP-glucuronosyltransferase 1-1 Losartan N2-glucuronide N-glucuronidation
UDP-glucuronosyltransferase 1-3 Losartan N2-glucuronide N-glucuronidation
UDP-glucuronosyltransferase 1-10 Losartan N2-glucuronide N-glucuronidation
UDP-glucuronosyltransferase 2B7 Losartan N2-glucuronide N-glucuronidation
UDP-glucuronosyltransferase 2B17 Losartan N2-glucuronide N-glucuronidation
Route of elimination After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites.
Half life The terminal t1/2 of losartan is 2 hours and that of E-3174 is 6-9 hours.
Clearance
  • 600 mL/min [Healthy volunteers after IV administration]
  • Renal cl=56 +/- 23 mL/min [Hypertensive adults given 50 mg once daily for 7 days]
  • Renal cl=53 +/- 33 mL/min [Hypertensive children (6-16 years old) given 0.7 mg/kg once daily for 7 days]
Toxicity Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD50= 1000 mg/kg (orally in rat)
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Melting point 183.5-184.5 oC
Experimental Properties
Property Value Source
water solubility 0.82 mg/L PhysProp
logP 6.1 PhysProp
Predicted Properties
Property Value Source
water solubility 4.70e-03 g/l ALOGPS
logP 4.50 ALOGPS
logP 5.08 ChemAxon Molconvert
logS -4.95 ALOGPS
pKa 14.27 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 92.51 ChemAxon Molconvert
rotatable bond count 8 ChemAxon Molconvert
refractivity 131.85 ChemAxon Molconvert
polarizability 44.86 ChemAxon Molconvert
药物相互作用
Drug Interaction
Amiloride Increased risk of hyperkalemia
Drospirenone Increased risk of hyperkalemia
Indomethacin Indomethacin decreases the effect of losartan
Lithium Losartan increases serum levels of lithium
Potassium Increased risk of hyperkalemia
Quinupristin This combination presents an increased risk of toxicity
Rifampin Rifampin decreases the effect of losartan
Spironolactone Increased risk of hyperkalemia
Tobramycin Increased risk of nephrotoxicity
Tolbutamide Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Losartan. Consider alternate therapy or monitor for changes in Losartan therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
Trandolapril The angiotensin II receptor blocker, Losartan, may increase the adverse effects of Trandolapril.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Tretinoin The moderate CYP2C8 inhibitor, Losartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Losartan is initiated, discontinued to dose changed.
Triamterene Increased risk of hyperkalemia
食物相互作用
  • Take without regard to meals. Take at same time each day. Food delays absorption, but does not affect the extent of absorption.

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