Identification
- Generic Name
- Efonidipine
- DrugBank Accession Number
- DB09235
- Background
Efonidipine is a calcium channel blocker of the dihydropyridine class, commercialized by Shionogi & Co. (Japan). Initially, it was marketed in 1995 under the trade name, Landel. The drug has been shown to block T-type in addition to L-type calcium channels 1,2. It has also been studied in atherosclerosis and acute renal failure 2. This drug is also known as NZ-105, and several studies have been done on its pharmacokinetics in animals 13.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
Structure for Efonidipine (DB09235)
- Weight
- Average: 631.666
Monoisotopic: 631.244737574 - Chemical Formula
- C34H38N3O7P
- Synonyms
- Efonidipine
- External IDs
- NZ-105
Pharmacology
- Indication
For the treatment of hypertension.
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Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Dihydropyridines (DHPs), act mainly on L-type calcium channels, essentially causing reflex tachycardia, which negatively affects cardiac function. This leads to a decrease in blood pressure and an increase in heart rate. Efonidipine acts on both L-type and T-type calcium channels. Because inhibition of T-type calcium channels in the sinoatrial (SA node) node attenuate reflex tachycardia, this drug favorably affects cardiac pacing. The effect of efonidipine on heart rate deserves special recognition with regard to reflex tachycardia, due to its unique effects in relation to other drugs in its class 5.
- Mechanism of action
This drug inhibits the L-type and T-type calcium channels, thereby leading to vasodilation and decreased automaticity of the heart. Efonidipine exerts negative chronotropic effects, decreasing heart rate. Acting on SA node cells by inhibiting T-type calcium channel activity, Efonidipine prolongs the late phase-4 depolarization of the sinoatrial node action potential, decreasing heart rate. This is associated with decreased myocardial oxygen demand and increases of blood flow to the coronary arteries and thereby attenuates myocardial ischemia. Efonidipine increases glomerular filtration rate (GFR) without increasing intra-glomerular pressure and filtration fraction 1,3,4 . This increase leads to the prevention of renal damage that is normally associated with hypertension.
Efonidipine increases the rate of renal sodium excretion via the suppression of aldosterone synthesis and aldosterone secretion from the adrenal glands. Aldosterone-induced renal parenchymal fibrosis is said to be suppressed by efonidipine 4.
L-type calcium channel blockers, such as efonidipine, preferentially dilate afferent arterioles in the kidney, whereas both L-/T-type and L-/N-type calcium channel blockers potently dilate both afferent and efferent arterioles. The distinct actions of calcium channel blockers on the renal microcirculation are demonstrated by changes in glomerular capillary pressure and subsequent renal injury: L-type calcium channel blockers favor an increase in glomerular capillary pressure, whereas L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. This supports the theory that L-Type/T-type calcium channel blockers may be of benefit in renal hypertension 4. Efonidipine is a long-acting medication due to a low dissociation constant 11.
Recent studies suggest that efonidipine reduces plasma aldosterone levels in patients on regular hemodialysis, which is of additional benefit to the cardiovascular protection by antihypertensive therapy with efonidipine in patients with end-stage renal disease 5.
Target Actions Organism UVoltage-dependent T-type calcium channel subunit alpha-1I antagonistHumans UVoltage-dependent L-type calcium channel subunit alpha-1C Not Available Humans AVoltage gated L-type calcium channel blockerHumans AVoltage-dependent calcium channel inhibitorHumans AVoltage-dependent T-type calcium channel inhibitorHumans AVoltage-dependent T-type calcium channel subunit alpha-1G inhibitorHumans AVoltage-dependent T-type calcium channel subunit alpha-1H inhibitorHumans - Absorption
The metabolism of efonidipine was studied in rats. The absorption ratio of radioactivity estimated from the sum of biliary and urinary excretions was found to be approximately 62% 14. The radioactivity was high in the gastrointestinal tract and liver, followed by the adrenal glands 14, suggesting high rates of metabolism in these regions.
The unchanged drug in the plasma accounted for 47.7% of radioactivity at 2hr after ingestion, demonstrating a lower first-pass effect in comparison with other drugs in the same class. In plasma, major metabolites of NZ-105 were: N-debenzylated compound (DBZ), N-dephenylated compound (DPH), oxidative deaminated compound (AL), AL-corresponding pyridine compound (ALP), unknown metabolite M-1 and M-25. NZ-105 was metabolized by N-debenzylation, N-dephenylation, oxidative deamination, ester hydrolysis and oxidation of 1, 4-dihydropyridine ring to its corresponding pyridine 14.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
It has been suggested that efonidipine is less likely to be subject to the first-pass than other members of its drug class, and and that its dihydropyridine ring is oxidized primarily after metabolism of the side chain 8. Efonidipine is highly lipophilic and this allows for its entry into the phospholipid-rich cell membrane and reach the dihydropyridine binding site of the calcium channel targets 10.
Efonidipine is mainly metabolized in the liver. Its metabolites are N-dephenylated Efonidipine (DPH), deaminated efonidipine (AL) and N-debenzylated Efonidipine (DBZ). Both metabolites behave as calcium antagonists. In one study, the vasodilating capabilities of DBZ and DPH were about two-thirds and one-third respectively than that of the unmetabolized drug. Research suggests that the majority of the pharmacological effect after oral dosing of efonidipine hydrochloride is due to unchanged drug and its metabolites play little role in its therapeutic effect.
In a study of six healthy volunteers, no significant amount of unchanged drug was excreted in urine. The urine samples collected for 24 h after oral efonidipine administration, 1.1% of the dose was excreted as deaminated-efonidipine, and 0.5% as a pyridine analogue of deaminated-efonidipine 14.
- Route of elimination
Efonidipine is also referred to as NZ-105 13 and has been found to be mainly eliminated by the biliary system 14.
- Half-life
The peak plasma concentration is attained at approximately 1.5 to 3.67 hours after ingestion. The half-life is measured to be about 4 hours 12.
- Clearance
Not Available
- Adverse Effects
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Ld50: >5 g/kg in rats, orally 6,15. Some common adverse effects include hot flashes, flushing of the face, and headache. Elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may also occur. Frequent urination, pedal edema, increased triglycerides have been found to occur in less than 0.1% of patients 16,15.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Efonidipine may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy. Abaloparatide The risk or severity of adverse effects can be increased when Abaloparatide is combined with Efonidipine. Abametapir The serum concentration of Efonidipine can be increased when it is combined with Abametapir. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Efonidipine. Acalabrutinib The serum concentration of Acalabrutinib can be increased when it is combined with Efonidipine. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Efonidipine hydrochloride 3BR983K69O 111011-53-1 OXVTXPCIJDYQIS-UHFFFAOYSA-N - International/Other Brands
- Landel (Shionogi & Co.) / NZ-105 / Selefodipine
Categories
- Drug Categories
- Agents causing hyperkalemia
- Antiarrhythmic agents
- Antihypertensive Agents
- Benzene Derivatives
- Bradycardia-Causing Agents
- Calcium Channel Blockers
- Calcium-Regulating Hormones and Agents
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Diuretics
- Hypotensive Agents
- Membrane Transport Modulators
- Natriuretic Agents
- Nitro Compounds
- Phenols
- Potential QTc-Prolonging Agents
- Pyridines
- QTc Prolonging Agents
- Vasodilating Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylbenzamines. These are aromatic compounds consisting of a benzyl group that is N-linked to a benzamine.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylmethylamines
- Direct Parent
- Phenylbenzamines
- Alternative Parents
- Dihydropyridinecarboxylic acids and derivatives / Nitrobenzenes / Aniline and substituted anilines / Benzylamines / Dialkylarylamines / Nitroaromatic compounds / Phosphonic acid diesters / Aralkylamines / Phosphonic acid esters / Vinylogous amides show 15 more
- Substituents
- Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzylamine / C-nitro compound show 36 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 40ZTP2T37Q
- CAS number
- 111011-63-3
- InChI Key
- NSVFSAJIGAJDMR-UHFFFAOYSA-N
- InChI
- InChI=1S/C34H38N3O7P/c1-24-30(33(38)42-19-18-36(28-15-9-6-10-16-28)21-26-12-7-5-8-13-26)31(27-14-11-17-29(20-27)37(39)40)32(25(2)35-24)45(41)43-22-34(3,4)23-44-45/h5-17,20,31,35H,18-19,21-23H2,1-4H3
- IUPAC Name
- 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2λ⁵-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
- SMILES
- CC1=C(C(C2=CC=CC(=C2)[N+]([O-])=O)C(=C(C)N1)P1(=O)OCC(C)(C)CO1)C(=O)OCCN(CC1=CC=CC=C1)C1=CC=CC=C1
References
- General References
- Tanaka H, Shigenobu K: Efonidipine hydrochloride: a dual blocker of L- and T-type ca(2+) channels. Cardiovasc Drug Rev. 2002 Winter;20(1):81-92. [Article]
- Nakano N, Ishimitsu T, Takahashi T, Inada H, Okamura A, Ohba S, Matsuoka H: Effects of efonidipine, an L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients. Int Heart J. 2010 May;51(3):188-92. [Article]
- Hasegawa K, Wakino S, Kanda T, Yoshioka K, Tatematsu S, Homma K, Takamatsu I, Sugano N, Hayashi K: Divergent action of calcium channel blockers on ATP-binding cassette protein expression. J Cardiovasc Pharmacol. 2005 Dec;46(6):787-93. [Article]
- Hayashi K, Homma K, Wakino S, Tokuyama H, Sugano N, Saruta T, Itoh H: T-type Ca channel blockade as a determinant of kidney protection. Keio J Med. 2010;59(3):84-95. [Article]
- Effects of efonidipine, an L- and T-Type dual calcium channel blocker, on heart rate and blood pressure in patients with mild to severe hypertension: an uncontrolled, open-label pilot study☆ [Link]
- Pharmaceutical Substances, 5th Edition, 2009 [Link]
- Pharmacokinetic Interaction between Warfarin and Efonidipine in Rats [Link]
- Clinical Efficacy of Efonidipine Hydrochloride, a T-type Calcium Channel Inhibitor, on Sympathetic Activities Examination Using Spectral Analysis of Heart Rate/Blood Pressure Variabilities and 123I-Metaiodobenzylguanidine Myocardial Scintigraphy [Link]
- DORSET CARDIOLOGY WORKING GROUP GUIDELINE FOR CALCIUM CHANNEL BLOCKERS IN HYPERTENSION [Link]
- Relationship between Lipophilicities of 1,4-Dihydropyridine Derivatives and Pharmacokinetic Interaction Strengths with Grapefruit Juice [Link]
- Effect of an L- and T-Type Calcium Channel Blocker on 24-Hour Systolic Blood Pressure and Heart Rate in Hypertensive Patients [Link]
- Efonidipine [Link]
- Drug profile: Efonidipine [Link]
- Studies on the Metabolic Fate of NZ-105. (I). Absorption, Distribution, Metabolism and Excretion after a Single Administration to Rats. [Link]
- Efonidipine [Link]
- CHEMICAL IDENTIFICATION [Link]
- External Links
- PubChem Compound
- 119171
- PubChem Substance
- 310265139
- ChemSpider
- 106463
- ChEBI
- 135859
- ChEMBL
- CHEMBL2074922
- Wikipedia
- Efonidipine
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count Not Available Completed Basic Science Endothelium, Vascular 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 746.9±60.0 °C https://www.chemsrc.com/en/searchResult/Efonidipine%20hydrochloride%20ethanolate/ water solubility poorly soluble https://www.ncbi.nlm.nih.gov/pubmed/27553261 - Predicted Properties
Property Value Source Water Solubility 0.000248 mg/mL ALOGPS logP 5.35 ALOGPS logP 5.44 Chemaxon logS -6.4 ALOGPS pKa (Strongest Acidic) 19.49 Chemaxon pKa (Strongest Basic) 2.33 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 120.24 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 175.4 m3·mol-1 Chemaxon Polarizability 64.96 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 220.91774 predictedDeepCCS 1.0 (2019) [M+H]+ 222.78268 predictedDeepCCS 1.0 (2019) [M+Na]+ 228.52309 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- Voltage-gated calcium channel activity
- Specific Function
- 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, hor...
- Gene Name
- CACNA1I
- Uniprot ID
- Q9P0X4
- Uniprot Name
- Voltage-dependent T-type calcium channel subunit alpha-1I
- Molecular Weight
- 245100.8 Da
References
- Tanaka H, Shigenobu K: Efonidipine hydrochloride: a dual blocker of L- and T-type ca(2+) channels. Cardiovasc Drug Rev. 2002 Winter;20(1):81-92. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- General Function
- Voltage-gated calcium channel activity
- Specific Function
- 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, hor...
- Gene Name
- CACNA1C
- Uniprot ID
- Q13936
- Uniprot Name
- Voltage-dependent L-type calcium channel subunit alpha-1C
- Molecular Weight
- 248974.1 Da
References
- Tanaka H, Shigenobu K: Efonidipine hydrochloride: a dual blocker of L- and T-type ca(2+) channels. Cardiovasc Drug Rev. 2002 Winter;20(1):81-92. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Voltage-gated calcium channel activity
- Specific Function
- 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, hor...
Components:
References
- Richard S: Vascular effects of calcium channel antagonists: new evidence. Drugs. 2005;65 Suppl 2:1-10. doi: 10.2165/00003495-200565002-00002. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Voltage-gated calcium channel activity
- Specific Function
- This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only...
Components:
References
- Shima E, Katsube M, Kato T, Kitagawa M, Hato F, Hino M, Takahashi T, Fujita H, Kitagawa S: Calcium channel blockers suppress cytokine-induced activation of human neutrophils. Am J Hypertens. 2008 Jan;21(1):78-84. doi: 10.1038/ajh.2007.13. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Scaffold protein binding
- Specific Function
- 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, hor...
Components:
References
- Richard S: Vascular effects of calcium channel antagonists: new evidence. Drugs. 2005;65 Suppl 2:1-10. doi: 10.2165/00003495-200565002-00002. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Scaffold protein binding
- Specific Function
- 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, hor...
- Gene Name
- CACNA1G
- Uniprot ID
- O43497
- Uniprot Name
- Voltage-dependent T-type calcium channel subunit alpha-1G
- Molecular Weight
- 262468.62 Da
References
- Furukawa T, Nukada T, Namiki Y, Miyashita Y, Hatsuno K, Ueno Y, Yamakawa T, Isshiki T: Five different profiles of dihydropyridines in blocking T-type Ca(2+) channel subtypes (Ca(v)3.1 (alpha(1G)), Ca(v)3.2 (alpha(1H)), and Ca(v)3.3 (alpha(1I))) expressed in Xenopus oocytes. Eur J Pharmacol. 2009 Jun 24;613(1-3):100-7. doi: 10.1016/j.ejphar.2009.04.036. Epub 2009 May 3. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Scaffold protein binding
- Specific Function
- 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, hor...
- Gene Name
- CACNA1H
- Uniprot ID
- O95180
- Uniprot Name
- Voltage-dependent T-type calcium channel subunit alpha-1H
- Molecular Weight
- 259160.2 Da
References
- Furukawa T, Nukada T, Namiki Y, Miyashita Y, Hatsuno K, Ueno Y, Yamakawa T, Isshiki T: Five different profiles of dihydropyridines in blocking T-type Ca(2+) channel subtypes (Ca(v)3.1 (alpha(1G)), Ca(v)3.2 (alpha(1H)), and Ca(v)3.3 (alpha(1I))) expressed in Xenopus oocytes. Eur J Pharmacol. 2009 Jun 24;613(1-3):100-7. doi: 10.1016/j.ejphar.2009.04.036. Epub 2009 May 3. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
Drug created at October 23, 2015 16:29 / Updated at February 02, 2024 22:52