Efonidipine

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
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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Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
UVoltage-dependent T-type calcium channel subunit alpha-1I
antagonist
Humans
UVoltage-dependent L-type calcium channel subunit alpha-1CNot AvailableHumans
AVoltage gated L-type calcium channel
blocker
Humans
AVoltage-dependent calcium channel
inhibitor
Humans
AVoltage-dependent T-type calcium channel
inhibitor
Humans
AVoltage-dependent T-type calcium channel subunit alpha-1G
inhibitor
Humans
AVoltage-dependent T-type calcium channel subunit alpha-1H
inhibitor
Humans
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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Toxicity

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
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbacavirEfonidipine may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
AbaloparatideThe risk or severity of adverse effects can be increased when Abaloparatide is combined with Efonidipine.
AbametapirThe serum concentration of Efonidipine can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Efonidipine.
AcalabrutinibThe serum concentration of Acalabrutinib can be increased when it is combined with Efonidipine.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Efonidipine hydrochloride3BR983K69O111011-53-1OXVTXPCIJDYQIS-UHFFFAOYSA-N
International/Other Brands
Landel (Shionogi & Co.) / NZ-105 / Selefodipine

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. Pharmaceutical Substances, 5th Edition, 2009 [Link]
  7. Pharmacokinetic Interaction between Warfarin and Efonidipine in Rats [Link]
  8. 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]
  9. DORSET CARDIOLOGY WORKING GROUP GUIDELINE FOR CALCIUM CHANNEL BLOCKERS IN HYPERTENSION [Link]
  10. Relationship between Lipophilicities of 1,4-Dihydropyridine Derivatives and Pharmacokinetic Interaction Strengths with Grapefruit Juice [Link]
  11. Effect of an L- and T-Type Calcium Channel Blocker on 24-Hour Systolic Blood Pressure and Heart Rate in Hypertensive Patients [Link]
  12. Efonidipine [Link]
  13. Drug profile: Efonidipine [Link]
  14. Studies on the Metabolic Fate of NZ-105. (I). Absorption, Distribution, Metabolism and Excretion after a Single Administration to Rats. [Link]
  15. Efonidipine [Link]
  16. CHEMICAL IDENTIFICATION [Link]
PubChem Compound
119171
PubChem Substance
310265139
ChemSpider
106463
ChEBI
135859
ChEMBL
CHEMBL2074922
Wikipedia
Efonidipine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedBasic ScienceEndothelium, Vascular1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)746.9±60.0 °C https://www.chemsrc.com/en/searchResult/Efonidipine%20hydrochloride%20ethanolate/
water solubilitypoorly solublehttps://www.ncbi.nlm.nih.gov/pubmed/27553261
Predicted Properties
PropertyValueSource
Water Solubility0.000248 mg/mLALOGPS
logP5.35ALOGPS
logP5.44Chemaxon
logS-6.4ALOGPS
pKa (Strongest Acidic)19.49Chemaxon
pKa (Strongest Basic)2.33Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area120.24 Å2Chemaxon
Rotatable Bond Count11Chemaxon
Refractivity175.4 m3·mol-1Chemaxon
Polarizability64.96 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-220.91774
predicted
DeepCCS 1.0 (2019)
[M+H]+222.78268
predicted
DeepCCS 1.0 (2019)
[M+Na]+228.52309
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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
  1. 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
  1. 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
  1. 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:
NameUniProt ID
Voltage-dependent calcium channel gamma-1 subunitQ06432
Voltage-dependent calcium channel gamma-2 subunitQ9Y698
Voltage-dependent calcium channel gamma-3 subunitO60359
Voltage-dependent calcium channel gamma-4 subunitQ9UBN1
Voltage-dependent calcium channel gamma-5 subunitQ9UF02
Voltage-dependent calcium channel gamma-6 subunitQ9BXT2
Voltage-dependent calcium channel gamma-7 subunitP62955
Voltage-dependent calcium channel gamma-8 subunitQ8WXS5
Voltage-dependent calcium channel subunit alpha-2/delta-1P54289
Voltage-dependent calcium channel subunit alpha-2/delta-2Q9NY47
Voltage-dependent calcium channel subunit alpha-2/delta-3Q8IZS8
Voltage-dependent calcium channel subunit alpha-2/delta-4Q7Z3S7
Voltage-dependent L-type calcium channel subunit alpha-1CQ13936
Voltage-dependent L-type calcium channel subunit alpha-1DQ01668
Voltage-dependent L-type calcium channel subunit alpha-1FO60840
Voltage-dependent L-type calcium channel subunit alpha-1SQ13698
Voltage-dependent L-type calcium channel subunit beta-1Q02641
Voltage-dependent L-type calcium channel subunit beta-2Q08289
Voltage-dependent L-type calcium channel subunit beta-3P54284
Voltage-dependent L-type calcium channel subunit beta-4O00305
Voltage-dependent N-type calcium channel subunit alpha-1BQ00975
Voltage-dependent P/Q-type calcium channel subunit alpha-1AO00555
Voltage-dependent R-type calcium channel subunit alpha-1EQ15878
Voltage-dependent T-type calcium channel subunit alpha-1GO43497
Voltage-dependent T-type calcium channel subunit alpha-1HO95180
Voltage-dependent T-type calcium channel subunit alpha-1IQ9P0X4
References
  1. 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
  1. 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
  1. 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
  1. 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
Substrate
Inhibitor
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
  1. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [Article]
  2. Pharmacokinetic Interaction between Warfarin and Efonidipine in Rats [Link]

Drug created at October 23, 2015 16:29 / Updated at February 02, 2024 22:52