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Identification
NameNisoldipine
Accession NumberDB00401  (APRD00635)
Typesmall molecule
Groupsapproved
Description

Nisoldipine is a 1,4-dihydropyridine calcium channel blocker. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, nisoldipine prevents calcium-dependent smooth muscle contraction and subsequent vasoconstriction. Nisoldipine may be used in alone or in combination with other agents in the management of hypertension.

Structure
Thumb
Synonyms
SynonymLanguageCode
isobutyl methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylateNot AvailableIUPAC
NisoldipinGermanINN
NisoldipinaNot AvailableDCIT
NisoldipineNot AvailableUSAN, DCF, JAN, BAN
NisoldipinoSpanishINN
NisoldipinumLatinINN
SaltsNot Available
Brand names
NameCompany
BaymycardBayer
Baymycard RRBayer
Bo PingRui Yang Pharm
Di Yi XinTasly
Ji Ni Le ErJiankang Pharmaceutical
NinobarucinChoseido Pharmaceutical
NisomynardYoshindo
RiohardTaiyo Pharmaceutical
RuidiNanjing Sanrui Pharmaceutical Co.
SularFirst Horizon
SyscorBayer
Brand mixturesNot Available
Categories
CAS number63675-72-9
WeightAverage: 388.4144
Monoisotopic: 388.16343651
Chemical FormulaC20H24N2O6
InChI KeyInChIKey=VKQFCGNPDRICFG-UHFFFAOYSA-N
InChI
InChI=1S/C20H24N2O6/c1-11(2)10-28-20(24)17-13(4)21-12(3)16(19(23)27-5)18(17)14-8-6-7-9-15(14)22(25)26/h6-9,11,18,21H,10H2,1-5H3
IUPAC Name
3-methyl 5-(2-methylpropyl) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC=C1[N+]([O-])=O)C(=O)OCC(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyridines and Derivatives
SubclassHydropyridines
Direct parentDihydropyridinecarboxylic Acids and Derivatives
Alternative parentsNitrobenzenes; Dicarboxylic Acids and Derivatives; Nitronic Acids; Carboxylic Acid Esters; Nitro Compounds; Ethers; Enolates; Enamines; Organic Oxoazanium Compounds; Polyamines
Substituentsbenzene; dicarboxylic acid derivative; carboxylic acid ester; nitro compound; nitronic acid; polyamine; carboxylic acid derivative; organic oxoazanium; ether; enolate; enamine; organonitrogen compound; amine
Classification descriptionThis compound belongs to the dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Pharmacology
IndicationFor the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
PharmacodynamicsNisoldipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nisoldipine is similar to other peripheral vasodilators. Nisoldipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Mechanism of actionBy deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
AbsorptionRelatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%.
Volume of distributionNot Available
Protein binding99%
Metabolism

Pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4.

Route of eliminationAlthough 60-80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine.
Half life7-12 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Nisoldipine Action PathwayDrug actionSMP00381
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9357
Blood Brain Barrier - 0.947
Caco-2 permeable + 0.6928
P-glycoprotein substrate Substrate 0.5548
P-glycoprotein inhibitor I Inhibitor 0.8824
P-glycoprotein inhibitor II Inhibitor 0.9239
Renal organic cation transporter Non-inhibitor 0.8925
CYP450 2C9 substrate Non-substrate 0.7874
CYP450 2D6 substrate Non-substrate 0.8929
CYP450 3A4 substrate Substrate 0.7366
CYP450 1A2 substrate Inhibitor 0.8782
CYP450 2C9 substrate Inhibitor 0.7826
CYP450 2D6 substrate Non-inhibitor 0.9141
CYP450 2C19 substrate Inhibitor 0.7804
CYP450 3A4 substrate Inhibitor 0.8414
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8982
Ames test Non AMES toxic 0.778
Carcinogenicity Non-carcinogens 0.5782
Biodegradation Not ready biodegradable 0.9335
Rat acute toxicity 2.6277 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8882
hERG inhibition (predictor II) Non-inhibitor 0.9175
Pharmacoeconomics
Manufacturers
  • Mylan pharmaceuticals inc
  • Shionogi pharma inc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coated, extended releaseOral10 mg
Tablet, film coated, extended releaseOral20 mg
Tablet, film coated, extended releaseOral30 mg
Tablet, film coated, extended releaseOral40 mg
Prices
Unit descriptionCostUnit
Sular 25.5 mg 24 Hour tablet6.84USDtablet
Sular 34 mg 24 Hour tablet6.84USDtablet
Sular 17 mg 24 Hour tablet6.48USDtablet
Sular 34 mg tablet5.64USDtablet
Sular 17 mg tablet5.17USDtablet
Nisoldipine er 30 mg tablet5.07USDtablet
Nisoldipine er 40 mg tablet5.07USDtablet
Sular 10 mg tablet5.04USDtablet
Sular 8.5 mg 24 Hour tablet5.04USDtablet
Nisoldipine er 20 mg tablet4.65USDtablet
Sular 25.5 mg tablet4.35USDtablet
Sular 8.5 mg tablet4.13USDtablet
Sular 20 mg tablet3.37USDtablet
Sular 30 mg 24 Hour tablet3.23USDtablet
Sular 40 mg 24 Hour tablet3.23USDtablet
Sular 30 mg tablet3.1USDtablet
Sular 40 mg tablet2.61USDtablet
Sular 10 mg 24 Hour tablet2.36USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States56268741994-11-302014-11-30
United States54221231995-06-062012-06-06
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP3.26MASUMOTO,K ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility5.77e-03 g/lALOGPS
logP3.63ALOGPS
logP3.06ChemAxon
logS-4.8ALOGPS
pKa (strongest basic)5.32ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count1ChemAxon
polar surface area110.45ChemAxon
rotatable bond count8ChemAxon
refractivity105.91ChemAxon
polarizability39.72ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Massimo Ferrari, Marcello Ghezzi, Manuel Alberelli, Alberto Ambrosini, “Industrial process for the synthesis of isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate (nisoldipine).” U.S. Patent US20050240022, issued October 27, 2005.

US20050240022
General Reference
  1. Mielcarek J, Grobelny P, Szamburska O: The effect of beta-carotene on the photostability of nisoldipine. Methods Find Exp Clin Pharmacol. 2005 Apr;27(3):167-71. Pubmed
  2. Missan S, Zhabyeyev P, Dyachok O, Jones SE, McDonald TF: Block of cardiac delayed-rectifier and inward-rectifier K+ currents by nisoldipine. Br J Pharmacol. 2003 Nov;140(5):863-70. Epub 2003 Oct 6. Pubmed
  3. Hamilton SF, Houle LM, Thadani U: Rapid-release and coat-core formulations of nisoldipine in treatment of hypertension, angina, and heart failure. Heart Dis. 1999 Nov-Dec;1(5):279-88. Pubmed
External Links
ResourceLink
KEGG DrugD00618
KEGG CompoundC07699
PubChem Compound4499
PubChem Substance46504546
ChemSpider4343
BindingDB50011689
Therapeutic Targets DatabaseDAP000595
PharmGKBPA450634
IUPHAR2524
Guide to Pharmacology2524
RxListhttp://www.rxlist.com/cgi/generic/nisoldipine.htm
Drugs.comhttp://www.drugs.com/cdi/nisoldipine-extended-release-tablets.html
WikipediaNisoldipine
ATC CodesC08CA07
AHFS Codes
  • 24:28.08
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid concurrent use of nisoldipine with strong inhibitors of CYP3A4, as the combination may lead to substantial increases in nisoldipine concentrations.
EtravirineNisoldipine, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
FosphenytoinPhenytoin decreases the efficiency of nisoldipine
PhenytoinPhenytoin decreases the efficiency of nisoldipine
QuinupristinThis combination presents an increased risk of toxicity
TelithromycinTelithromycin may reduce clearance of Nisoldipine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Nisoldipine if Telithromycin is initiated, discontinued or dose changed.
ThiopentalThe CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Nisoldipine, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Nisoldipine if Thiopental is initiated, discontinued or dose changed.
TipranavirTipranavir, co-administered with Ritonavir, may alter the concentration of Nisoldipine. Monitor for efficacy and adverse/toxic effects of Nisoldipine.
TreprostinilAdditive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of nisoldipine by decreasing its metabolism. Concomitant therapy should be avoided.
Food Interactions
  • Do not take with grapefruit juice as this has been shown to interfere with nisoldipine metabolism, resulting in a mean increase in Cmax of about 3-fold (up to about 7-fold) and AUC of almost 2-fold (up to 5-fold).

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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Hu H, Marban E: Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Mol Pharmacol. 1998 May;53(5):902-7. Pubmed
  3. Morel N, Buryi V, Feron O, Gomez JP, Christen MO, Godfraind T: The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits. Br J Pharmacol. 1998 Nov;125(5):1005-12. Pubmed
  4. Striessnig, J. (2004). Ca 2+ channel blockers. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin, Germany: Springer.
  5. Wei X, Pan S, Lang W, Kim H, Schneider T, Perez-Reyes E, Birnbaumer L: Molecular determinants of cardiac Ca2+ channel pharmacology. Subunit requirement for the high affinity and allosteric regulation of dihydropyridine binding. J Biol Chem. 1995 Nov 10;270(45):27106-11. 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. 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.

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 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. 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

5. 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

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. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 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

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, Sakaeda T, Tanigawara Y, Nishiguchi K, Ohmoto N, Horinouchi M, Komada F, Ohnishi N, Yokoyama T, Okumura K: Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression. Eur J Pharm Sci. 2002 Aug;16(3):159-65. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on March 13, 2014 11:32