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Identification
NameLisinopril
Accession NumberDB00722  (APRD00560)
Typesmall molecule
Groupsapproved, investigational
Description

Lisinopril is a potent, competitive inhibitor of angiotensin-converting enzyme (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). Lisinopril may be used to treat hypertension and symptomatic congestive heart failure, to improve survival in certain individuals following myocardial infarction, and to prevent progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

Structure
Thumb
Synonyms
SynonymLanguageCode
LisinoprilFrench/German/SpanishINN
LisinoprilumLatinINN
SaltsNot Available
Brand names
NameCompany
AcebitorGlaxoSmithKline
AceminAstraZeneca
AcerbonAstraZeneca
Acinoprilsanofi-aventis
BellisinRanbaxy
BioprilBiochem
DaprilMedochemie
FibsolSigma
FisoprilSanofi-Aventis
HiprilMicro Labs
LinoprilKlinger (Brazil)
LisiprilHexal (Czech Republic), Orion (Finland)
NopertenDexa (Indonesia)
PresitenMagnachem
PrinivilMerck Frosst
RanolipRanbaxy
RanoprilRanbaxy
RantexBiotech
SinoprenRanbaxy
SinoprilEczacibasi (Russia)
TensoprilMerck
ZestrilAstraZeneca
Brand mixtures
Brand NameIngredients
AcercompLisinopril and Hydrochlorothiazide
Acerdil DLisinopril and Hydrochlorothiazide
Adco-Zetomax COLisinopril and Hydrochlorothiazide
Amchek LLisinopril and Amlodipine
AmlaceLisinopril and Amlodipine
Amlodac-LLisinopril and Amlodipine
Amlopres-L Lisinopril and Amlodipine
Amlot-LLisinopril and Amlodipine
Amlovas-LLisinopril and Amlodipine
Amtas-LPLisinopril and Amlodipine
Lisinopril Complisinopril + hydrochlorothiazide
Prinzidelisinopril + hydrochlorothiazide
Zestoretic Tab 10/12.5mglisinopril + hydrochlorothiazide
Zestoretic Tab 20/12.5mglisinopril + hydrochlorothiazide
Zestoretic Tab 20/25mglisinopril + hydrochlorothiazide
CategoriesNot Available
CAS number83915-83-7
WeightAverage: 405.4879
Monoisotopic: 405.226371117
Chemical FormulaC21H31N3O5
InChI KeyInChIKey=RLAWWYSOJDYHDC-BZSNNMDCSA-N
InChI
InChI=1S/C21H31N3O5/c22-13-5-4-9-16(19(25)24-14-6-10-18(24)21(28)29)23-17(20(26)27)12-11-15-7-2-1-3-8-15/h1-3,7-8,16-18,23H,4-6,9-14,22H2,(H,26,27)(H,28,29)/t16-,17-,18-/m0/s1
IUPAC Name
(2S)-1-[(2S)-6-amino-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}hexanoyl]pyrrolidine-2-carboxylic acid
SMILES
NCCCC[C@H](N[C@@H](CCC1=CC=CC=C1)C(O)=O)C(=O)N1CCC[C@H]1C(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 Amides; Phenylpropylamines; Pyrrolidine Carboxylic Acids; Amino Fatty Acids; Dicarboxylic Acids and Derivatives; Tertiary Carboxylic Acid Amides; Tertiary Amines; Polyols; Dialkylamines; Polyamines; Carboxylic Acids; Enolates; Monoalkylamines
Substituentsn-acyl-alpha-amino acid; n-acyl-alpha amino acid or derivative; alpha-amino acid amide; alpha-amino acid or derivative; phenylpropylamine; pyrrolidine carboxylic acid; pyrrolidine carboxylic acid or derivative; dicarboxylic acid derivative; benzene; tertiary carboxylic acid amide; pyrrolidine; carboxamide group; polyol; tertiary amine; carboxylic acid; secondary amine; polyamine; enolate; secondary aliphatic amine; primary aliphatic amine; amine; primary 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 hypertension and symptomatic congestive heart failure. May be used in conjunction with thrombolytic agents, aspirin and/or β-blockers to improve survival in hemodynamically stable individuals following myocardial infarction. May be used to slow the progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.
PharmacodynamicsLisinopril is an orally active ACE inhibitor that antagonizes 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 further sustain the effects of lisinopril 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. Lisinopril, one of the few ACE inhibitors that is not a prodrug, 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. Lisinopril 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.
AbsorptionApproximately 25%, but widely variable between individuals (6 to 60%) in all doses tested (5-80 mg); absorption is unaffected by food
Volume of distributionNot Available
Protein bindingLisinopril does not appear to be bound to serum proteins other than ACE.
Metabolism

Does not undergo metabolism, excreted unchanged in urine.

Route of eliminationLisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.
Half lifeEffective half life of accumulation following multiple dosing is 12 hours.
Clearance
  • 10 L/h [child weighting 30 kg receiving doses of 0.1 to 0.2 mg/kg]
ToxicitySymptoms of overdose include severe hypotension, electrolyte disturbances, and renal failure. LD50= 2000 mg/kg(orally in rat). Most frequent adverse effects include headache, dizziness, cough, fatigue and diarrhea.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.6426
Blood Brain Barrier - 0.8815
Caco-2 permeable - 0.7605
P-glycoprotein substrate Substrate 0.6515
P-glycoprotein inhibitor I Non-inhibitor 0.9512
P-glycoprotein inhibitor II Non-inhibitor 0.969
Renal organic cation transporter Non-inhibitor 0.8574
CYP450 2C9 substrate Non-substrate 0.8793
CYP450 2D6 substrate Non-substrate 0.7622
CYP450 3A4 substrate Non-substrate 0.725
CYP450 1A2 substrate Non-inhibitor 0.8999
CYP450 2C9 substrate Non-inhibitor 0.9708
CYP450 2D6 substrate Non-inhibitor 0.9653
CYP450 2C19 substrate Non-inhibitor 0.8266
CYP450 3A4 substrate Non-inhibitor 0.907
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9821
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.9389
Biodegradation Not ready biodegradable 0.6844
Rat acute toxicity 1.8723 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9641
hERG inhibition (predictor II) Non-inhibitor 0.8708
Pharmacoeconomics
Manufacturers
  • Actavis elizabeth llc
  • Apotex inc etobicoke site
  • Aurobindo pharma ltd
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Lek pharmaceuticals d d
  • Lupin ltd
  • Mylan pharmaceuticals inc
  • Ranbaxy pharmaceuticals inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Vintage pharmaceuticals llc
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Wockhardt ltd
  • Merck research laboratories div merck co inc
  • Astrazeneca uk ltd
Packagers
Dosage forms
FormRouteStrength
TabletOral10 mg
TabletOral2.5 mg
TabletOral20 mg
TabletOral30 mg
TabletOral40 mg
TabletOral5 mg
Prices
Unit descriptionCostUnit
Prinivil 90 20 mg tablet Bottle111.71USDbottle
Prinzide 30 20-12.5 mg tablet Bottle45.99USDbottle
Prinivil 30 2.5 mg tablet Bottle22.48USDbottle
Lisinopril 100% powder21.6USDg
Zestril 40 mg tablet2.53USDtablet
Zestril 30 mg tablet2.41USDtablet
Prinivil 40 mg tablet2.23USDtablet
Zestoretic 20-25 mg tablet2.01USDtablet
Zestoretic 20-12.5 mg tablet2.0USDtablet
Prinzide 20-25 mg tablet1.98USDtablet
Zestoretic 10-12.5 mg tablet1.89USDtablet
Zestoretic 10-12.5 tablet1.75USDtablet
Lisinopril 30 mg tablet1.53USDtablet
Lisinopril 40 mg tablet1.44USDtablet
Prinzide 20-12.5 mg tablet1.38USDtablet
Prinzide 10-12.5 mg tablet1.37USDtablet
Zestril 20 mg tablet1.37USDtablet
Zestril 10 mg tablet1.33USDtablet
Zestoretic 20-25 tablet1.28USDtablet
Zestril 5 mg tablet1.28USDtablet
Zestoretic 20-12.5 tablet1.26USDtablet
Lisinopril 20 mg tablet1.09USDtablet
Prinivil 20 mg tablet1.05USDtablet
Zestril 2.5 mg tablet1.04USDtablet
Lisinopril 10 mg tablet1.01USDtablet
Prinivil 10 mg tablet1.01USDtablet
Lisinopril 5 mg tablet0.99USDtablet
Prinivil 5 mg tablet0.96USDtablet
Apo-Lisinopril 20 mg Tablet0.71USDtablet
Co Lisinopril 20 mg Tablet0.71USDtablet
Mylan-Lisinopril 20 mg Tablet0.71USDtablet
Novo-Lisinopril (Type P) 20 mg Tablet0.71USDtablet
Novo-Lisinopril (Type Z) 20 mg Tablet0.71USDtablet
Pms-Lisinopril 20 mg Tablet0.71USDtablet
Ran-Lisinopril 20 mg Tablet0.71USDtablet
Ratio-Lisinopril P 20 mg Tablet0.71USDtablet
Ratio-Lisinopril Z 20 mg Tablet0.71USDtablet
Sandoz Lisinopril 20 mg Tablet0.71USDtablet
Lisinopril 2.5 mg tablet0.65USDtablet
Apo-Lisinopril 10 mg Tablet0.59USDtablet
Co Lisinopril 10 mg Tablet0.59USDtablet
Mylan-Lisinopril 10 mg Tablet0.59USDtablet
Novo-Lisinopril (Type P) 10 mg Tablet0.59USDtablet
Novo-Lisinopril (Type Z) 10 mg Tablet0.59USDtablet
Pms-Lisinopril 10 mg Tablet0.59USDtablet
Ran-Lisinopril 10 mg Tablet0.59USDtablet
Ratio-Lisinopril P 10 mg Tablet0.59USDtablet
Ratio-Lisinopril Z 10 mg Tablet0.59USDtablet
Sandoz Lisinopril 10 mg Tablet0.59USDtablet
Apo-Lisinopril 5 mg Tablet0.49USDtablet
Co Lisinopril 5 mg Tablet0.49USDtablet
Mylan-Lisinopril 5 mg Tablet0.49USDtablet
Novo-Lisinopril (Type P) 5 mg Tablet0.49USDtablet
Novo-Lisinopril (Type Z) 5 mg Tablet0.49USDtablet
Pms-Lisinopril 5 mg Tablet0.49USDtablet
Ran-Lisinopril 5 mg Tablet0.49USDtablet
Ratio-Lisinopril P 5 mg Tablet0.49USDtablet
Ratio-Lisinopril Z 5 mg Tablet0.49USDtablet
Sandoz Lisinopril 5 mg Tablet0.49USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubility9.7E+004 mg/LMERCK INDEX (1996)
logP-1.01MERCK INDEX (1996); pH 7
pKa2.5 (at 25 °C)MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
water solubility2.16e-01 g/lALOGPS
logP-1.2ALOGPS
logP-3.1ChemAxon
logS-3.3ALOGPS
pKa (strongest acidic)3.17ChemAxon
pKa (strongest basic)10.21ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count4ChemAxon
polar surface area132.96ChemAxon
rotatable bond count12ChemAxon
refractivity107.37ChemAxon
polarizability43.5ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Vincenzo Cannata, Valeriano Merli, Stefano Saguatti, “Process for the production of alkoxycarbonyldipeptides intermediates in the synthesis of the lisinopril.” U.S. Patent US6166217, issued September, 1972.

US6166217
General Reference
  1. Abdelmalek MF, Douglas DD: Lisinopril-induced isolated visceral angioedema: review of ACE-inhibitor-induced small bowel angioedema. Dig Dis Sci. 1997 Apr;42(4):847-50. Pubmed
  2. Hasslacher C: Influence of the ACE inhibitor lisinopril on blood pressure, metabolism, and renal function parameter in hypertensive type II diabetic patients: a postmarketing surveillance study. J Diabetes Complications. 1996 May-Jun;10(3):136-8. Pubmed
  3. Nielsen SE, Sugaya T, Tarnow L, Lajer M, Schjoedt KJ, Astrup AS, Baba T, Parving HH, Rossing P: Tubular and glomerular injury in diabetes and the impact of ACE inhibition. Diabetes Care. 2009 Sep;32(9):1684-8. Epub 2009 Jun 5. Pubmed
  4. Patchett AA, Harris E, Tristram EW, Wyvratt MJ, Wu MT, Taub D, Peterson ER, Ikeler TJ, ten Broeke J, Payne LG, Ondeyka DL, Thorsett ED, Greenlee WJ, Lohr NS, Hoffsommer RD, Joshua H, Ruyle WV, Rothrock JW, Aster SD, Maycock AL, Robinson FM, Hirschmann R, Sweet CS, Ulm EH, Gross DM, Vassil TC, Stone CA: A new class of angiotensin-converting enzyme inhibitors. Nature. 1980 Nov 20;288(5788):280-3. Pubmed
External Links
ResourceLink
KEGG DrugD00362
PubChem Compound5362119
PubChem Substance46504893
ChemSpider4514933
ChEBI43755
ChEMBLCHEMBL1237
Therapeutic Targets DatabaseDAP000587
PharmGKBPA450242
HETLPR
Drug Product Database2217538
RxListhttp://www.rxlist.com/cgi/generic/lisinop.htm
Drugs.comhttp://www.drugs.com/lisinopril.html
PDRhealthhttp://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=zes1498.html&contentName=Zestril&contentId=861
WikipediaLisinopril
ATC CodesNot Available
AHFS Codes
  • 24:32.04
PDB Entries
FDA labelshow(267 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
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 lisinopril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of lisinopril.
  • Lisinopril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.
  • Take without regard to meals.

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. Andujar-Sanchez M, Jara-Perez V, Camara-Artigas A: Thermodynamic determination of the binding constants of angiotensin-converting enzyme inhibitors by a displacement method. FEBS Lett. 2007 Jul 24;581(18):3449-54. Epub 2007 Jun 27. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. 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
  5. Tellez-Sanz R, Garcia-Fuentes L, Baron C: Calorimetric analysis of lisinopril binding to angiotensin I-converting enzyme. FEBS Lett. 1998 Feb 13;423(1):75-80. Pubmed

2. Angiotensin-converting enzyme 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Angiotensin-converting enzyme 2 Q9BYF1 Details

References:

  1. Parish RC, Miller LJ: Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update. Drug Saf. 1992 Jan-Feb;7(1):14-31. Pubmed
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  3. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. 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

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. Tsuji A: Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on January 08, 2014 09:42