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Identification
Name Nisoldipine
Accession Number DB00401 (APRD00635)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Nisoldipin
Nisoldipino [INN-Spanish]
Nisoldipinum [INN-Latin]
Salts Not Available
Brand names
Name Company
Baymycard
Nisocor
Sular First Horizon
Syscor
Zadipina
Brand mixtures Not Available
Categories
  • Antihypertensive Agents
  • Vasodilator Agents
  • Calcium Channel Blockers
CAS number 63675-72-9
Weight Average: 388.4144
Monoisotopic: 388.16343651
Chemical Formula C20H24N2O6
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Nitrobenzenes
Substructures
  • Dihydropyridines
  • Carboxylic Acids and Derivatives
  • Nitrobenzenes
  • Acetates
  • Oxoazaniums
  • Ethers
  • Benzene and Derivatives
  • Nitro compounds
  • Enamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anilines
Pharmacology
Indication For the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Pharmacodynamics Nisoldipine, 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 action By 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.
Absorption Relatively 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 distribution Not Available
Protein binding 99%
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 elimination Although 60-80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine.
Half life 7-12 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00381 Nisoldipine Pathway SMP00381
Pharmacoeconomics
Manufacturers
  • Mylan pharmaceuticals inc
  • Shionogi pharma inc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated, extended release Oral 10 mg
Tablet, film coated, extended release Oral 20 mg
Tablet, film coated, extended release Oral 30 mg
Tablet, film coated, extended release Oral 40 mg
Prices
Unit description Cost Unit
Sular 25.5 mg 24 Hour tablet 6.84 USD tablet
Sular 34 mg 24 Hour tablet 6.84 USD tablet
Sular 17 mg 24 Hour tablet 6.48 USD tablet
Sular 34 mg tablet 5.64 USD tablet
Sular 17 mg tablet 5.17 USD tablet
Nisoldipine er 30 mg tablet 5.07 USD tablet
Nisoldipine er 40 mg tablet 5.07 USD tablet
Sular 10 mg tablet 5.04 USD tablet
Sular 8.5 mg 24 Hour tablet 5.04 USD tablet
Nisoldipine er 20 mg tablet 4.65 USD tablet
Sular 25.5 mg tablet 4.35 USD tablet
Sular 8.5 mg tablet 4.13 USD tablet
Sular 20 mg tablet 3.37 USD tablet
Sular 30 mg 24 Hour tablet 3.23 USD tablet
Sular 40 mg 24 Hour tablet 3.23 USD tablet
Sular 30 mg tablet 3.1 USD tablet
Sular 40 mg tablet 2.61 USD tablet
Sular 10 mg 24 Hour tablet 2.36 USD tablet
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Patents
Country Patent Number Approved Expires (estimated)
United States 5626874 1994-11-30 2014-11-30
United States 5422123 1995-06-06 2012-06-06
Properties
State solid
Experimental Properties
Property Value Source
logP 3.26 MASUMOTO,K ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 5.77e-03 g/l ALOGPS
logP 3.63 ALOGPS
logP 3.06 ChemAxon
logS -4.8 ALOGPS
pKa (strongest basic) 5.32 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 110.45 ChemAxon
rotatable bond count 8 ChemAxon
refractivity 105.91 ChemAxon
polarizability 39.72 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00618 Link_out
KEGG Compound C07699 Link_out
PubChem Compound 4499 Link_out
PubChem Substance 46504546 Link_out
ChemSpider 4343 Link_out
BindingDB 50011689 Link_out
Therapeutic Targets Database DAP000595 Link_out
PharmGKB PA450634 Link_out
IUPHAR 2524 Link_out
Guide to Pharmacology 2524 Link_out
RxList http://www.rxlist.com/cgi/generic/nisoldipine.htm Link_out
Drugs.com http://www.drugs.com/cdi/nisoldipine-extended-release-tablets.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Nisoldipine Link_out
ATC Codes
  • C08CA07
AHFS Codes
  • 24:28.08
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Conivaptan CYP3A4 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.
Fosphenytoin Phenytoin decreases the efficiency of nisoldipine
Phenytoin Phenytoin decreases the efficiency of nisoldipine
Quinupristin This combination presents an increased risk of toxicity
Telithromycin Telithromycin 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.
Thiopental The 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.
Tipranavir Tipranavir, co-administered with Ritonavir, may alter the concentration of Nisoldipine. Monitor for efficacy and adverse/toxic effects of Nisoldipine.
Treprostinil Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.
Voriconazole Voriconazole, 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).
Targets

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

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds

Organism class: human
UniProt ID: Q13936 Link_out
Gene: CACNA1C 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. 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

Pharmacological action: yes
Actions: inhibitor

Calcium channel protein which plays an important role in excitation-contraction coupling

Organism class: human
UniProt ID: P54289 Link_out
Gene: CACNA2D1 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. 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

Pharmacological action: yes
Actions: inhibitor

The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting

Organism class: human
UniProt ID: Q08289 Link_out
Gene: CACNB2 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. 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

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA)

Organism class: human
UniProt ID: Q01668 Link_out
Gene: CACNA1D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle

Organism class: human
UniProt ID: Q13698 Link_out
Gene: CACNA1S Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

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. 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

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
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, 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 February 08, 2013 16:19