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Identification
NamePerindopril
Accession NumberDB00790  (APRD01178)
Typesmall molecule
Groupsapproved
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
Perindopril ErbumineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AceonSolvay
CoversylServier
Brand mixtures
Brand NameIngredients
Coversyl Plusperindopril erbumine + indapamide
Preteraxperindopril erbumine + indapamide
Categories
CAS number107133-36-8
WeightAverage: 368.4678
Monoisotopic: 368.231122144
Chemical FormulaC19H32N2O5
InChI KeyIPVQLZZIHOAWMC-QXKUPLGCSA-N
InChI
InChI=1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1
IUPAC Name
(2S,3aS,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid
SMILES
[H][C@]12C[C@H](N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@@]1([H])CCCC2)C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids and Derivatives
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsN-acyl-alpha Amino Acids; Alpha Amino Acid Esters; Alpha Amino Acid Amides; Indoles and Derivatives; Pyrrolidine Carboxylic Acids; Fatty Acid Esters; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Carboxylic Acid Esters; Carboxylic Acids; Dialkylamines; Polyamines; Enolates; Ethers
Substituentsn-acyl-alpha-amino acid; n-acyl-alpha amino acid or derivative; alpha-amino acid ester; alpha-amino acid amide; alpha-amino acid or derivative; indole or derivative; pyrrolidine carboxylic acid; pyrrolidine carboxylic acid or derivative; fatty acid ester; dicarboxylic acid derivative; pyrrolidine; tertiary carboxylic acid amide; tertiary amine; carboxamide group; carboxylic acid ester; secondary aliphatic amine; secondary amine; polyamine; ether; enolate; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the peptides. These are compounds containing an amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon of one to the nitrogen atom of another.
Pharmacology
IndicationFor 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.
PharmacodynamicsPerindopril 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 actionThere 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.
AbsorptionRapidly 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 distributionNot Available
Protein bindingPerindoprilat, 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.

SubstrateEnzymesProduct
Perindopril
Not Available
Perindopril Acyl-beta-D-glucuronideDetails
Perindopril
Not Available
PerindoprilatDetails
Perindopril
Not Available
Perindoprilat glucuronideDetails
Route of eliminationPerindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine.
Half lifePerindopril, 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]
ToxicityThe 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
PathwayCategorySMPDB ID
Perindopril Action PathwayDrug actionSMP00152
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9156
Blood Brain Barrier - 0.8411
Caco-2 permeable - 0.7871
P-glycoprotein substrate Substrate 0.6826
P-glycoprotein inhibitor I Inhibitor 0.5
P-glycoprotein inhibitor II Inhibitor 0.8589
Renal organic cation transporter Non-inhibitor 0.919
CYP450 2C9 substrate Non-substrate 0.8638
CYP450 2D6 substrate Non-substrate 0.8542
CYP450 3A4 substrate Substrate 0.549
CYP450 1A2 substrate Non-inhibitor 0.8796
CYP450 2C9 substrate Non-inhibitor 0.8612
CYP450 2D6 substrate Non-inhibitor 0.9088
CYP450 2C19 substrate Non-inhibitor 0.8375
CYP450 3A4 substrate Non-inhibitor 0.7142
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5951
Ames test Non AMES toxic 0.8814
Carcinogenicity Non-carcinogens 0.9266
Biodegradation Not ready biodegradable 0.9082
Rat acute toxicity 1.9432 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9839
hERG inhibition (predictor II) Non-inhibitor 0.8678
Pharmacoeconomics
Manufacturers
  • Abbott products inc
  • Aurobindo pharma ltd
  • Ivax pharmaceuticals inc
  • Lupin ltd
  • Roxane laboratories inc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral2 mg
Tablet, film coatedOral4 mg
Tablet, film coatedOral8 mg
Prices
Unit descriptionCostUnit
Aceon 8 mg tablet3.14USDtablet
Perindopril erbumine 8 mg tablet2.8USDtablet
Aceon 4 mg tablet2.58USDtablet
Perindopril erbumine 4 mg tablet2.3USDtablet
Aceon 2 mg tablet2.22USDtablet
Perindopril erbumine 2 mg tablet1.98USDtablet
Coversyl 8 mg Tablet1.23USDtablet
Coversyl 4 mg Tablet0.88USDtablet
Coversyl 2 mg Tablet0.7USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States51623621992-11-102009-11-10
Canada24732052010-05-182023-01-22
Canada13411962001-03-062018-03-06
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2.6Not Available
Predicted Properties
PropertyValueSource
water solubility1.22e+00 g/lALOGPS
logP0.56ALOGPS
logP0.63ChemAxon
logS-2.5ALOGPS
pKa (strongest acidic)3.79ChemAxon
pKa (strongest basic)5.48ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area95.94ChemAxon
rotatable bond count9ChemAxon
refractivity95.69ChemAxon
polarizability40ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Michel Vincent, Jean Baliarda, Bernard Marchand, Georges Remond, “Process for the industrial synthesis of perindopril.” U.S. Patent US4914214, issued April 03, 1990.

US4914214
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
External Links
ResourceLink
KEGG DrugD03753
KEGG CompoundC07706
PubChem Compound107807
PubChem Substance46508767
ChemSpider96956
ChEBI8024
ChEMBLCHEMBL1581
Therapeutic Targets DatabaseDNC001114
PharmGKBPA450877
Drug Product Database2246624
RxListhttp://www.rxlist.com/cgi/generic/aceon.htm
Drugs.comhttp://www.drugs.com/cdi/perindopril.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ace1543.shtml
WikipediaPerindopril
ATC CodesC09AA04
AHFS Codes
  • 24:32.04
PDB EntriesNot Available
FDA labelshow(149 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AmilorideIncreased risk of hyperkalemia
Azilsartan medoxomilPharmacodynamic synergism: dual blockade of renin-angiotensin system. Increases risks of hypotension, hyperkalemia, renal impairment.
DrospirenoneIncreased risk of hyperkalemia
IcatibantIcatibant may attenuate the antihypertensive effect of ACE inhibitors by pharmacodynamic antagonism. Monitor concomitant therapy closely.
LithiumThe ACE inhibitor increases serum levels of lithium
PotassiumIncreased risk of hyperkalemia
SpironolactoneIncreased risk of hyperkalemia
TizanidineTizanidine increases the risk of hypotension with the ACE inhibitor
TobramycinIncreased risk of nephrotoxicity
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TriamtereneIncreased risk of hyperkalemia
Food Interactions
  • 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.

Targets

1. Angiotensin-converting enzyme

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Angiotensin-converting enzyme P12821 Details

References:

  1. Alfakih K, Hall AS: Perindopril. Expert Opin Pharmacother. 2006 Jan;7(1):63-71. Pubmed
  2. Brugts JJ, Ferrari R, Simoons ML: Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2009 Apr;7(4):345-60. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet. 2002;41(3):207-24. Pubmed

Enzymes

1. Cholinesterase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cholinesterase P06276 Details

References:

  1. Mehta A, Iyer L, Parmar S, Shah G, Goyal R: Oculohypotensive effect of perindopril in acute and chronic models of glaucoma in rabbits. Can J Physiol Pharmacol. 2010 May;88(5):595-600. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K: Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci. 2002 Feb 15;70(13):1491-500. Pubmed

2. Solute carrier family 15 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 1 P46059 Details

References:

  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed

3. Solute carrier family 15 member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 15 member 2 Q16348 Details

References:

  1. Knutter I, Wollesky C, Kottra G, Hahn MG, Fischer W, Zebisch K, Neubert RH, Daniel H, Brandsch M: Transport of angiotensin-converting enzyme inhibitors by H+/peptide transporters revisited. J Pharmacol Exp Ther. 2008 Nov;327(2):432-41. Epub 2008 Aug 19. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12