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Identification
NameIsradipine
Accession NumberDB00270  (APRD00298)
Typesmall molecule
Groupsapproved
Description

Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. It is structurally related to felodipine, nifedipine, and nimodipine and is the most potent calcium-channel blocking agent of the DHP class. Isradipine binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and arterial smooth muscle cells. It exhibits greater selectivity towards arterial smooth muscle cells owing to alternative splicing of the alpha-1 subunit of the channel and increased prevalence of inactive channels in smooth muscle cells. Isradipine may be used to treat mild to moderate essential hypertension.

Structure
Thumb
Synonyms
SynonymLanguageCode
IsradipinoSpanishNot Available
IsradipinumLatinNot Available
SaltsNot Available
Brand names
NameCompany
ClivotenItalfarmaco (Italy)
DynaCircNovartis (Hong Kong, Malaysia, Mexico, New Zealand, South Africa, Singapore, Thailand, Turkey, United States)
Dynacirc CRReliant, GlaxoSmithKline
EsradinSigma-Tau (Italy)
LomirNovartis (Austria, Brazil, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, Netherlands, Norway, Poland, Russia, Sweden), Sankyo (Belgium, Italy), Daiichi Sankyo (Portugal, Switzerland), Mizar (Spain)
PrescalNovartis (United Kingdom)
Brand mixturesNot Available
Categories
CAS number75695-93-1
WeightAverage: 371.3871
Monoisotopic: 371.148120797
Chemical FormulaC19H21N3O5
InChI KeyHMJIYCCIJYRONP-UHFFFAOYSA-N
InChI
InChI=1S/C19H21N3O5/c1-9(2)26-19(24)15-11(4)20-10(3)14(18(23)25-5)16(15)12-7-6-8-13-17(12)22-27-21-13/h6-9,16,20H,1-5H3
IUPAC Name
3-methyl 5-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC2=NON=C12)C(=O)OC(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzoxadiazoles
SubclassNot Available
Direct parentBenzoxadiazoles
Alternative parentsDihydropyridinecarboxylic Acids and Derivatives; Benzene and Substituted Derivatives; Dicarboxylic Acids and Derivatives; Furazans; Carboxylic Acid Esters; Enamines; Enolates; Ethers; Polyamines
Substituentsdihydropyridine; benzene; dicarboxylic acid derivative; hydropyridine; oxadiazole; azole; furazan; carboxylic acid ester; carboxylic acid derivative; enamine; ether; polyamine; enolate; organonitrogen compound
Classification descriptionThis compound belongs to the benzoxadiazoles. These are organic compounds containing a benzene fused to an oxadiazole ring (a five-member ring with two carbon atoms, one nitrogen atom, and one oxygen atom).
Pharmacology
IndicationFor the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics.
PharmacodynamicsIsradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure.
Mechanism of actionIsradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells.
AbsorptionIsradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%.
Volume of distributionNot Available
Protein binding95%
Metabolism

Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine.

Route of eliminationApproximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces.
Half life8 hours
ClearanceNot Available
ToxicitySymptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Isradipine Action PathwayDrug actionSMP00378
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9965
Blood Brain Barrier - 0.8439
Caco-2 permeable + 0.8867
P-glycoprotein substrate Substrate 0.5855
P-glycoprotein inhibitor I Inhibitor 0.9322
P-glycoprotein inhibitor II Inhibitor 0.8669
Renal organic cation transporter Non-inhibitor 0.884
CYP450 2C9 substrate Non-substrate 0.8522
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6631
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Inhibitor 0.8949
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Inhibitor 0.8994
CYP450 3A4 substrate Inhibitor 0.796
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8557
Ames test Non AMES toxic 0.5158
Carcinogenicity Non-carcinogens 0.8043
Biodegradation Not ready biodegradable 0.9747
Rat acute toxicity 2.3960 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8699
hERG inhibition (predictor II) Non-inhibitor 0.6895
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
  • Actavis totowa llc
  • Watson laboratories inc
  • Glaxosmithkline llc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral2.5 mg
CapsuleOral5 mg
Tablet, extended releaseOral10 mg
Tablet, extended releaseOral5 mg
Prices
Unit descriptionCostUnit
DynaCirc CR 10 mg 24 Hour tablet5.59USDtablet
Dynacirc cr 10 mg tablet4.41USDtablet
DynaCirc CR 5 mg 24 Hour tablet3.0USDtablet
Dynacirc cr 5 mg tablet2.88USDtablet
DynaCirc 5 mg capsule2.31USDcapsule
Isradipine 5 mg capsule2.0USDcapsule
DynaCirc 2.5 mg capsule1.59USDcapsule
Isradipine 2.5 mg capsule1.39USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point168-170 °CNot Available
water solubilityPractically insoluble (< 10 mg/L at 37 °C)Not Available
logP4.28SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility2.28e-01 g/lALOGPS
logP3ALOGPS
logP2ChemAxon
logS-3.2ALOGPS
pKa (strongest basic)5.33ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count1ChemAxon
polar surface area103.55ChemAxon
rotatable bond count6ChemAxon
refractivity100.08ChemAxon
polarizability37.39ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Fletcher H, Roberts G, Mullings A, Forrester T: An open trial comparing isradipine with hydralazine and methyl dopa in the treatment of patients with severe pre-eclampsia. J Obstet Gynaecol. 1999 May;19(3):235-8. Pubmed
  2. Ganz M, Mokabberi R, Sica DA: Comparison of blood pressure control with amlodipine and controlled-release isradipine: an open-label, drug substitution study. J Clin Hypertens (Greenwich). 2005 Apr;7(4 Suppl 1):27-31. Pubmed
  3. Hattori T, Wang PL: Calcium antagonist isradipine-induced calcium influx through nonselective cation channels in human gingival fibroblasts. Eur J Med Res. 2006 Mar 27;11(3):93-6. Pubmed
  4. Johnson BA, Roache JD, Ait-Daoud N, Wallace C, Wells L, Dawes M, Wang Y: Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine’s subjective and reinforcing effects. Int J Neuropsychopharmacol. 2005 Jun;8(2):203-13. Pubmed
External Links
ResourceLink
KEGG DrugD00349
PubChem Compound3784
PubChem Substance46505034
ChemSpider3652
Therapeutic Targets DatabaseDAP000134
PharmGKBPA450131
RxListhttp://www.rxlist.com/cgi/generic2/israd.htm
Drugs.comhttp://www.drugs.com/cdi/isradipine.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dyn1152.shtml
WikipediaIsradipine
ATC CodesC08CA03
AHFS Codes
  • 24:28.08
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(57.4 KB)
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
QuinupristinThis combination presents an increased risk of toxicity
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelithromycinTelithromycin may reduce clearance of Isradipine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Isradipine if Telithromycin is initiated, discontinued or dose changed.
ThiopentalThe CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Isradipine, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Isradipine if Thiopental is initiated, discontinued or dose changed.
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
TipranavirTipranavir may decrease the metabolism and clearance of the calcium channel blocker, Isradipine. Monitor for changes in Isradipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of isradipine by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of isradipine if voriconazole is initiated, discontinued or dose changed.
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol decanoateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food InteractionsNot Available

Targets

1. Voltage-dependent L-type calcium channel subunit alpha-1C

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1C Q13936 Details

References:

  1. Berjukow S, Marksteiner R, Gapp F, Sinnegger MJ, Hering S: Molecular mechanism of calcium channel block by isradipine. Role of a drug-induced inactivated channel conformation. J Biol Chem. 2000 Jul 21;275(29):22114-20. Pubmed
  2. Hitzl M, Striessnig J, Neuhuber B, Flucher BE: A mutation in the beta interaction domain of the Ca(2+) channel alpha(1C) subunit reduces the affinity of the (+)-[(3)H]isradipine binding site. FEBS Lett. 2002 Jul 31;524(1-3):188-92. Pubmed
  3. Zuhlke RD, Bouron A, Soldatov NM, Reuter H: Ca2+ channel sensitivity towards the blocker isradipine is affected by alternative splicing of the human alpha1C subunit gene. FEBS Lett. 1998 May 8;427(2):220-4. Pubmed

2. Voltage-dependent calcium channel subunit alpha-2/delta-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent calcium channel subunit alpha-2/delta-1 P54289 Details

References:

  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Voltage-dependent L-type calcium channel subunit beta-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit beta-2 Q08289 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Striessnig, J. (2004). Ca 2+ channel blockers. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin, Germany: Springer.

4. Voltage-dependent T-type calcium channel subunit alpha-1H

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent T-type calcium channel subunit alpha-1H O95180 Details

References:

  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. Epub 2008 Oct 30. Pubmed

5. Voltage-dependent calcium channel subunit alpha-2/delta-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent calcium channel subunit alpha-2/delta-2 Q9NY47 Details

References:

  1. Cohen CJ, Spires S, Van Skiver D: Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists. J Gen Physiol. 1992 Oct;100(4):703-28. Pubmed
  2. Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. Epub 2008 Oct 30. Pubmed

6. Voltage-dependent L-type calcium channel subunit alpha-1D

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1D Q01668 Details

References:

  1. Koschak A, Reimer D, Huber I, Grabner M, Glossmann H, Engel J, Striessnig J: alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem. 2001 Jun 22;276(25):22100-6. Epub 2001 Apr 2. Pubmed
  2. Sinnegger-Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, Hoda JC, Sartori SB, Striessnig J: Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009 Feb;75(2):407-14. Epub 2008 Nov 24. Pubmed

7. Voltage-dependent L-type calcium channel subunit alpha-1S

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent L-type calcium channel subunit alpha-1S Q13698 Details

References:

  1. Peterson BZ, Catterall WA: Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 Channels are modulated by calcium in the pore. Mol Pharmacol. 2006 Aug;70(2):667-75. Epub 2006 May 4. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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
  2. Lexicomp

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Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 18:05