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Identification
Name Enalapril
Accession Number DB00584 (APRD00510)
Type small molecule
Groups approved
Description

Enalapril is a prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is rapidly metabolized in the liver to enalaprilat following oral administration. Enalaprilat 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). Enalapril may be used to treat essential or renovascular hypertension and symptomatic congestive heart failure.
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Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Enalapril Maleate
Enalaprila [INN-Spanish]
Enalaprilat
Enalaprilum [INN-Latin]
Salts Not Available
Brand names
Name Company
Bonuten
Gadopril Gador (Argentina)
Kinfil Nova Argentia (Argentina)
Vasotec Merck Frosst (Canada)
Vasotec IV Sandoz (Canada)
Brand mixtures
Brand Name Ingredients
Lexxel enalapril maleate + felodipine
Vaseretic enalapril maleate + hydrochlorothiazide
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 75847-73-3
Weight Average: 376.4467
Monoisotopic: 376.199822016
Chemical Formula C20H28N2O5
InChI Key InChIKey=GBXSMTUPTTWBMN-XIRDDKMYSA-N
InChI
InChI=1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1
Plain Text
IUPAC Name
(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid
SMILES
CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the treatment of essential or renovascular hypertension and symptomatic congestive heart failure. It may be used alone or in combination with thiazide diuretics.
Pharmacodynamics Enalapril is a prodrug that is rapidly metabolized by liver esterases to enalaprilat following oral administration. Enalapril itself has little pharmacologic activity. Enalaprilat 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 enalaprilat 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. Enalaprilat, the principle active metabolite of enalapril, 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. Enalapril 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. Enalaprilat's affinity for ACE is approximately 200,000 times greater than that of ATI and 300-1000 times greater than that enalapril.
Absorption 55-75%, absorption is unaffected by food; enalaprilat (clinically administered IV) is poorly absorbed, 3-12%, due to its high polarity.
Volume of distribution Not Available
Protein binding 50-60% of enalaprilat is bound to plasma proteins
Metabolism
~ 60% of absorbed dose is extensively hydrolyzed to enalaprilat, primarily by liver esterases
Route of elimination Excretion of enalapril is primarily renal.
Half life < 2 hours for unchanged enalapril in health individuals, may be increased in those with congestive heart failure (3.4 and 5.8 hours for single 5- and 10-mg doses, respectively). The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours.
Clearance Not Available
Toxicity Overdosage may result in marked hypotension and stupor. Most common adverse effects include hypotension, headache, dizziness and fatigue.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00148 Enalapril Pathway SMP00148
Pharmacoeconomics
Manufacturers
  • Apotex inc
  • Apothecon inc div bristol myers squibb
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Krka dd novo mesto
  • Lek pharmaceuticals d d
  • Mylan pharmaceuticals inc
  • Ranbaxy laboratories ltd
  • Sandoz inc
  • Taro pharmaceutical industries ltd
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Wockhardt americas inc
  • Biovail laboratories international srl
  • Bedford laboratories div ben venue laboratories inc
  • Hikma farmaceutica (portugal) sa
  • Hospira inc
  • Teva parenteral medicines inc
Packagers
Dosage forms
Form Route Strength
Injection, solution Intravenous 1.25 mg/ml
Tablet Oral 10 mg
Tablet Oral 2.5 mg
Tablet Oral 20 mg
Tablet Oral 5 mg
Prices
Unit description Cost Unit
Enalapril maleate powder 9.18 USD g
Enalaprilat 1.25 mg/ml vial 3.6 USD ml
Vasotec 20 mg tablet 3.36 USD tablet
Vaseretic 10-25 mg tablet 3.15 USD tablet
Vasotec 10 mg tablet 2.63 USD tablet
Vasotec 5 mg tablet 2.08 USD tablet
Vasotec 2.5 mg tablet 1.65 USD tablet
Enalapril maleate 20 mg tablet 1.56 USD tablet
Vaseretic 5-12.5 mg tablet 1.49 USD tablet
Vasotec 20 mg Tablet 1.34 USD tablet
Vasotec 10 mg Tablet 1.11 USD tablet
Enalapril maleate 10 mg tablet 1.09 USD tablet
Enalapril maleate 5 mg tablet 1.03 USD tablet
Vasotec 5 mg Tablet 0.92 USD tablet
Enalapril maleate 2.5 mg tablet 0.82 USD tablet
Vasotec 2.5 mg Tablet 0.78 USD tablet
Apo-Enalapril 20 mg Tablet 0.75 USD tablet
Co Enalapril 20 mg Tablet 0.75 USD tablet
Mylan-Enalapril 20 mg Tablet 0.75 USD tablet
Novo-Enalapril 20 mg Tablet 0.75 USD tablet
Pms-Enalapril 20 mg Tablet 0.75 USD tablet
Ratio-Enalapril 20 mg Tablet 0.75 USD tablet
Sandoz Enalapril 20 mg Tablet 0.75 USD tablet
Taro-Enalapril 20 mg Tablet 0.75 USD tablet
Apo-Enalapril 10 mg Tablet 0.62 USD tablet
Co Enalapril 10 mg Tablet 0.62 USD tablet
Mylan-Enalapril 10 mg Tablet 0.62 USD tablet
Novo-Enalapril 10 mg Tablet 0.62 USD tablet
Pms-Enalapril 10 mg Tablet 0.62 USD tablet
Ratio-Enalapril 10 mg Tablet 0.62 USD tablet
Sandoz Enalapril 10 mg Tablet 0.62 USD tablet
Taro-Enalapril 10 mg Tablet 0.62 USD tablet
Apo-Enalapril 5 mg Tablet 0.52 USD tablet
Co Enalapril 5 mg Tablet 0.52 USD tablet
Mylan-Enalapril 5 mg Tablet 0.52 USD tablet
Novo-Enalapril 5 mg Tablet 0.52 USD tablet
Pms-Enalapril 5 mg Tablet 0.52 USD tablet
Ratio-Enalapril 5 mg Tablet 0.52 USD tablet
Sandoz Enalapril 5 mg Tablet 0.52 USD tablet
Taro-Enalapril 5 mg Tablet 0.52 USD tablet
Apo-Enalapril 2.5 mg Tablet 0.44 USD tablet
Co Enalapril 2.5 mg Tablet 0.44 USD tablet
Mylan-Enalapril 2.5 mg Tablet 0.44 USD tablet
Novo-Enalapril 2.5 mg Tablet 0.44 USD tablet
Pms-Enalapril 2.5 mg Tablet 0.44 USD tablet
Ratio-Enalapril 2.5 mg Tablet 0.44 USD tablet
Sandoz Enalapril 2.5 mg Tablet 0.44 USD tablet
Taro-Enalapril 2.5 mg Tablet 0.44 USD tablet
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Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 143-144.5 °C Not Available
water solubility 1.64E+004 mg/L (at 25 °C) MCFARLAND,JW ET AL. (2001)
logP 0.07 HANSCH,C ET AL. (1995)
Caco2 permeability -5.64 ADME Research, USCD
pKa 2.97 (the carboxyl group) and 5.35 (the amine group) at 25°C Not Available
Predicted Properties
Property Value Source
water solubility 2.13e-01 g/l ALOGPS
logP 0.19 ALOGPS
logP 0.59 ChemAxon
logS -3.2 ALOGPS
pKa (strongest acidic) 3.67 ChemAxon
pKa (strongest basic) 5.2 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 95.94 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 99.57 ChemAxon
polarizability 40.41 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. D.P. Ip and G.S. Brenner, in K. Florey (Editor), Analytical Profiles of Drug Substances, Vol. 16, Aca- demic Press, London, 1987, pp. 207-243.
External Links
Resource Link
KEGG Compound C06977 Link_out
ChEBI 4784 Link_out
ChEMBL 4784 Link_out
Therapeutic Targets Database DAP001374 Link_out
PharmGKB PA449456 Link_out
HET EAL Link_out
Drug Product Database 2019906 Link_out
RxList http://www.rxlist.com/cgi/generic/enalap.htm Link_out
Drugs.com http://www.drugs.com/enalapril.html Link_out
PDRhealth http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=Vas1477.html&contentName=Vasotec&contentId=6 Link_out
Wikipedia http://en.wikipedia.org/wiki/Enalapril Link_out
ATC Codes
  • C09AA02
AHFS Codes
  • 24:32.04
PDB Entries
FDA label show (939 KB)
MSDS Not Available
Interactions
Drug Interactions
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
Rifampin Rifampin, a strong CYP3A4 inducer, may increase the metabolism of enalapril. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of enalapril if rifampin is initiated, discontinued or dose changed.
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
Food Interactions
  • Enalapril decreases the excretion of potassium. Salt substitutes containing potassium increase the risk of hyperkalemia.
  • Herbs that may attenuate the antihypertensive effect of enalapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of enalapril.
  • Take without regard to meals.
Targets

1. Angiotensin-converting enzyme

Pharmacological action: yes
Actions: inhibitor

Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator

Organism class: human
UniProt ID: P12821 Link_out
Gene: ACE Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Liu YH, Liu LY, Wu JX, Chen SX, Sun YX: Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. J Cardiovasc Pharmacol. 2006 Jan;47(1):82-8. Pubmed
  4. Natesh R, Schwager SL, Evans HR, Sturrock ED, Acharya KR: Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry. 2004 Jul 13;43(27):8718-24. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Oligopeptide transporter, small intestine isoform

Actions: substrate, inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Han H, de Vrueh RL, Rhie JK, Covitz KM, Smith PL, Lee CP, Oh DM, Sadee W, Amidon GL: 5’-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 1998 Aug;15(8):1154-9. Pubmed
  2. Han HK, Rhie JK, Oh DM, Saito G, Hsu CP, Stewart BH, Amidon GL: CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs. J Pharm Sci. 1999 Mar;88(3):347-50. Pubmed
  3. Temple CS, Boyd CA: Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter. Biochim Biophys Acta. 1998 Aug 14;1373(1):277-81. Pubmed
  4. Tsuji A: Transporter-mediated Drug Interactions. Drug Metab Pharmacokinet. 2002;17(4):253-74. Pubmed

3. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. Pubmed

4. Solute carrier family 22 member 8

Actions: inhibitor

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kobayashi Y, Ohshiro N, Tsuchiya A, Kohyama N, Ohbayashi M, Yamamoto T: Renal transport of organic compounds mediated by mouse organic anion transporter 3 (mOat3): further substrate specificity of mOat3. Drug Metab Dispos. 2004 May;32(5):479-83. Pubmed

5. Solute carrier family 22 member 7

Actions: inhibitor

Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha- ketoglutarate

UniProt ID: Q9Y694 Link_out
Gene: SLC22A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, Yamamoto T: Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol. 2002 Jul;62(1):7-14. Pubmed
  2. Sekine T, Cha SH, Tsuda M, Apiwattanakul N, Nakajima N, Kanai Y, Endou H: Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett. 1998 Jun 12;429(2):179-82. Pubmed

6. Solute carrier organic anion transporter family member 1A2

Actions: substrate

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Abu-Zahra TN, Wolkoff AW, Kim RB, Pang KS: Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes. Drug Metab Dispos. 2000 Jul;28(7):801-6. Pubmed
  2. Pang KS, Wang PJ, Chung AY, Wolkoff AW: The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein. Hepatology. 1998 Nov;28(5):1341-6. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19