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药品详细

Perindopril(培哚普利)

化学结构式图
中文名
培哚普利
英文名
Perindopril
分子式
C19H32N2O5
化学名
(2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
分子量
Average: 368.4678
Monoisotopic: 368.231122144
CAS号
107133-36-8
ATC分类
C09A 未知
药物类型
small molecule
阶段
approved
商品名
Aceon (Solvay);Coversyl (Servier);
同义名
Perindopril Erbumine;
基本介绍

Perindopril is a nonsulfhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to perindoprilat, its active metabolite, following oral administration. Perindoprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Perindopril may be used to treat mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.

生产厂家
  • Abbott products inc
  • Aurobindo pharma ltd
  • Ivax pharmaceuticals inc
  • Lupin ltd
  • Roxane laboratories inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Hurst M, Jarvis B: Perindopril: an updated review of its use in hypertension. Drugs. 2001;61(6):867-96. Pubmed
  2. Jastrzebskal M, Widecka K, Naruszewicz M, Ciechanowicz A, Janczak-Bazan A, Foltynska A, Goracy I, Chetstowski K, Wesotowska T: Effects of perindopril treatment on hemostatic function in patients with essential hypertension in relation to angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms. Nutr Metab Cardiovasc Dis. 2004 Oct;14(5):259-69. Pubmed
  3. Parker E, Aarons L, Rowland M, Resplandy G: The pharmacokinetics of perindoprilat in normal volunteers and patients: influence of age and disease state. Eur J Pharm Sci. 2005 Sep;26(1):104-13. Pubmed
  4. Simpson D, Noble S, Goa KL: Perindopril: in congestive heart failure. Drugs. 2002;62(9):1367-77; discussion 1378-9. Pubmed
  5. Yasumatsu R, Nakashima T, Masuda M, Ito A, Kuratomi Y, Nakagawa T, Komune S: Effects of the angiotensin-I converting enzyme inhibitor perindopril on tumor growth and angiogenesis in head and neck squamous cell carcinoma cells. J Cancer Res Clin Oncol. 2004 Oct;130(10):567-73. Epub 2004 Jul 27. Pubmed
  6. Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H: The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001 Apr;7(4):1073-8. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Carboxylic Acids and Derivatives
  • Polypeptides
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Polypeptides
  • Heterocyclic compounds
  • Carboxamides and Derivatives
  • Amino Acids
适应症
ANTIHYPERTENSIVES 降血压;
药理
Indication For the treatment of mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce the cardiovascular risk of individuals with hypertension or post-myocardial infarction and stable coronary disease.
Pharmacodynamics Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of the RAAS. The 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 the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure.
Mechanism of action There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Absorption Rapidly absorbed with peak plasma concentrations occurring approximately 1 hour after oral administration. Bioavailability is 65-75%. Following absorption, perindopril is hydrolyzed to perindoprilat, which has an average bioavailability of 20%. The rate and extent of absorption is unaffected by food. However, food decreases the extent of biotransformation to peridoprilat and reduces its bioavailability by 35%.
Volume of distribution Not Available
Protein binding Perindoprilat, 10-20% bound to plasma proteins
Metabolism
Extensively metabolized, with only 4-12% of the dose recovered in urine following oral administration. Six metabolites have been identified: perindoprilat, perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams. Only perindoprilat is pharmacologically active. Peridoprilat and perindoprilat glucuronide are the two main circulating metabolites.

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

Substrate Enzymes Product
Perindopril
    		Perindopril Acyl-beta-D-glucuronide Details
    Perindopril
      		Perindoprilat Details
      Perindopril
        		Perindoprilat glucuronide Details
        Route of elimination Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine.
        Half life Perindopril, 1.2 hours; Peridoprilat, 30-120 hours. The long half life of peridoprilat is due to its slow dissociation from ACE binding sites.
        Clearance
        • 219 – 362 mL/min [oral administration]
        Toxicity The most likely symptom of overdose is severe hypotension. The most common adverse effects observed in controlled clinical trials include cough, digestive symptoms, fatigue, headache, and dizziness.
        Affected organisms
        • Humans and other mammals
        Pathways
        Pathway Name SMPDB ID
        Smp00152 Perindopril Pathway SMP00152
        理化性质
        Properties
        State solid
        Experimental Properties
        Property Value Source
        logP 2.6 Not Available
        Predicted Properties
        Property Value Source
        water solubility 1.22e+00 g/l ALOGPS
        logP 0.56 ALOGPS
        logP 0.63 ChemAxon
        logS -2.5 ALOGPS
        pKa (strongest acidic) 3.79 ChemAxon
        pKa (strongest basic) 5.48 ChemAxon
        physiological charge -1 ChemAxon
        hydrogen acceptor count 5 ChemAxon
        hydrogen donor count 2 ChemAxon
        polar surface area 95.94 ChemAxon
        rotatable bond count 9 ChemAxon
        refractivity 95.69 ChemAxon
        polarizability 40 ChemAxon
        药物相互作用
        Drug Interaction
        Amiloride Increased risk of hyperkalemia
        Azilsartan medoxomil Pharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
        Drospirenone Increased risk of hyperkalemia
        Icatibant Icatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
        Lithium The ACE inhibitor increases serum levels of lithium
        Potassium Increased risk of hyperkalemia
        Spironolactone Increased risk of hyperkalemia
        Tizanidine Tizanidine increases the risk of hypotension with the ACE inhibitor
        Tobramycin Increased risk of nephrotoxicity
        Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
        Triamterene Increased risk of hyperkalemia
        食物相互作用
        • Herbs that may attenuate the antihypertensive effect of perindopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
        • High salt intake may attenuate the antihypertensive effect of perindopril.
        • Perindopril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.
        • Take without regard to meals.

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