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Identification
Name Trandolapril
Accession Number DB00519 (APRD01269)
Type small molecule
Groups approved
Description

Trandolapril is a non-sulhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to its biologically active diacid form, trandolaprilat, in the liver. Trandolaprilat inhibits 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). Trandolapril may be used to treat mild to moderate hypertension, to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, as an adjunct treatment for congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Trandolaprilum [Latin]
Brand names
  • Mavik (Abbott)
Brand name mixtures
  • Tarka (trandolapril + verapamil hydrochloride)
Categories
  • Antihypertensive Agents
  • Angiotensin-converting Enzyme Inhibitors
CAS number 87679-37-6
Weight Average: 430.5372
Monoisotopic: 430.246772208
Chemical Formula C24H34N2O5
InChI Key InChIKey=VXFJYXUZANRPDJ-WTNASJBWSA-N
InChI
InChI=1S/C24H34N2O5/c1-3-31-24(30)19(14-13-17-9-5-4-6-10-17)25-16(2)22(27)26-20-12-8-7-11-18(20)15-21(26)23(28)29/h4-6,9-10,16,18-21,25H,3,7-8,11-15H2,1-2H3,(H,28,29)/t16-,18+,19-,20-,21-/m0/s1
Plain Text
IUPAC Name
(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-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](CCC3=CC=CC=C3)C(=O)OCC)[C@@]1([H])CCCC2)C(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Polypeptides
  • Phenylpropylamines
Substructures
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Pyrrolidines
  • Ethers
  • Benzene and Derivatives
  • Polypeptides
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Amino Acids
Pharmacology
Indication For the treatment of mild to moderate hypertension, as an adjunct in the treatment of congestive heart failure (CHF), to improve survival following myocardial infarction (MI) in individuals who are hemodynamically stable and demonstrate symptoms of left ventricular systolic dysfunction or signs of CHF within a few days following acute MI, and to slow progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.
Pharmacodynamics Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part 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 via 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 trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention.
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. Trandolaprilat, the active metabolite of trandolapril, 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. Trandolaprilat 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 ~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14%
Volume of distribution
  • 18 L
Protein binding Serum protein binding of trandolapril is ~ 80% (independent of concentration and not saturable) while that of trandolaprilat is 65 to 94% (concentration-dependent and saturable).
Metabolism

Cleavage of the ester group of trandolapril, primarily in the liver, is responsible for conversion to trandolaprilat, the active metabolite. Seven other metabolites, including diketopiperazine and glucuronide conjugated derivatives of trandolapril and trandolaprilat, have been identified.

Route of elimination After oral administration of trandolapril, about 33% of parent drug and metabolites are recovered in urine, mostly as trandolaprilat, with about 66% in feces.
Half life The elimination half lives of trandolapril and trandolaprilat are about 6 and 10 hours, respectively, but, similar to all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase that involves a small fraction of administered drug. This likely represents drug binding to plasma and tissue ACE. The effective half life of elimination for trandolaprilat is 16-24 hours.
Clearance
  • 52 L/h [After approximately 2 mg IV doses]
Toxicity Most likely clinical manifestations of overdose are symptoms of severe hypotension. Most common adverse effects include cough, headache and dizziness. The oral LD50 of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00157 Trandolapril Pathway SMP00157
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
  • Aurobindo pharma ltd
  • Cipla ltd
  • Corepharma llc
  • Dr reddys laboratories ltd
  • Epic pharma llc
  • Invagen pharmaceuticals inc
  • Lupin ltd
  • Mylan pharmaceuticals inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral 0.5 mg
Capsule Oral 1 mg
Capsule Oral 2 mg
Capsule Oral 4 mg
Prices
Unit description Cost Unit
Tarka 1-240 mg Controlled Release Tabs 3.46 USD tab
Tarka 4-240 mg Controlled Release Tabs 3.4 USD tab
Tarka 1-240 mg tablet sa 3.33 USD tablet
Tarka 2-180 mg tablet sa 3.33 USD tablet
Tarka 2-240 mg Controlled Release Tabs 3.33 USD tab
Tarka 2-240 mg tablet sa 3.33 USD tablet
Tarka 4-240 mg tablet sa 3.33 USD tablet
Tarka 2-180 mg Controlled Release Tabs 3.29 USD tab
Mavik 2 mg tablet 1.61 USD tablet
Mavik 4 mg tablet 1.61 USD tablet
Mavik 1 mg tablet 1.47 USD tablet
Trandolapril 1 mg tablet 1.24 USD tablet
Trandolapril 2 mg tablet 1.23 USD tablet
Trandolapril 4 mg tablet 1.23 USD tablet
Mavik 4 mg Capsule 1.03 USD capsule
Mavik 2 mg Capsule 0.83 USD capsule
Mavik 1 mg Capsule 0.72 USD capsule
Mavik 0.5 mg Capsule 0.42 USD capsule
Patents
Country Patent Number Approved Expires
United States 5744496 1995-04-28 2015-04-28
Canada 2023089 2003-01-14 2010-08-10
Canada 1341206 2001-03-20 2018-03-20
Properties
State solid
Melting point 119-123oC
Experimental Properties
Property Value Source
logP 3.5 PhysProp
Predicted Properties
Property Value Source
water solubility 2.07e-02 g/l ALOGPS
logP 1.31 ALOGPS
logP 1.93 ChemAxon Molconvert
logS -4.32 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 95.94 ChemAxon Molconvert
rotatable bond count 10 ChemAxon Molconvert
refractivity 115.79 ChemAxon Molconvert
polarizability 46.79 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Berl T: Review: renal protection by inhibition of the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst. 2009 Mar;10(1):1-8. Pubmed
  2. Conen H, Brunner HR: Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor. Am Heart J. 1993 May;125(5 Pt 2):1525-31. Pubmed
  3. Diaz A, Ducharme A: Update on the use of trandolapril in the management of cardiovascular disorders. Vasc Health Risk Manag. 2008;4(6):1147-58. Pubmed
  4. Guay DR: Trandolapril: a newer angiotensin-converting enzyme inhibitor. Clin Ther. 2003 Mar;25(3):713-75. Pubmed
  5. Jouquey S, Stepniewski JP, Hamon G: Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy. J Cardiovasc Pharmacol. 1994;23 Suppl 4:S16-8. Pubmed
  6. Reynolds NA, Wagstaff AJ, Keam SJ: Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension. Drugs. 2005;65(13):1893-914. Pubmed
  7. Rubio-Guerra AF, Vargas-Robles H, Vargas-Ayala G, Rodriguez-Lopez L, Escalante-Acosta BA: The effect of trandolapril and its fixed-dose combination with verapamil on circulating adhesion molecules levels in hypertensive patients with type 2 diabetes. Clin Exp Hypertens. 2008 Oct;30(7):682-8. Pubmed
  8. Sanbe A, Tanonaka K, Kobayasi R, Takeo S: Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol. 1995 Oct;27(10):2209-22. Pubmed
  9. Torp-Pedersen C, Kober L: Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet. 1999 Jul 3;354(9172):9-12. Pubmed
  10. Trandolapril: an ACE inhibitor for treatment of hypertension. Med Lett Drugs Ther. 1996 Nov 22;38(988):104-5. Pubmed
  11. Wiseman LR, McTavish D: Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension. Drugs. 1994 Jul;48(1):71-90. Pubmed
  12. Zannad F: Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? Drugs. 1993;46 Suppl 2:172-81; discussion 182. Pubmed
External Links
Resource Link
KEGG Drug D00383 Link_out
PubChem Compound 5484727 Link_out
PubChem Substance 46508300 Link_out
ChemSpider 4588590 Link_out
Therapeutic Targets Database DAP000583 Link_out
PharmGKB PA451737 Link_out
Drug Product Database 2239267 Link_out
RxList http://www.rxlist.com/cgi/generic3/mavik.htm Link_out
Drugs.com http://www.drugs.com/cdi/trandolapril.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/tar1425.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Trandolapril Link_out
ATC Codes
  • C09AA10
AHFS Codes
  • 24:32.04
PDB Entries Not Available
FDA label Not Available
MSDS show (57.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Herbs that may attenuate the antihypertensive effect of trandolapril include: bayberry, blue cohash, cayenne, ephedra, ginger, ginseng (American), kola and licorice.
  • High salt intake may attenuate the antihypertensive effect of trandolapril.
  • Take without regard to meals.
  • Trandolapril may decrease the excretion of potassium. Salt substitutes containing potassium may increase the risk of hyperkalemia.
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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Piepho RW: Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm. 2000 Oct 1;57 Suppl 1:S3-7. Pubmed
  3. 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
Transporters

1. Oligopeptide transporter, small intestine isoform

Actions: substrate

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. 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

2. Oligopeptide transporter, kidney isoform

Actions: substrate

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides

UniProt ID: Q16348 Link_out
Gene: SLC15A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:40

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.