Identification

Name
Efonidipine
Accession Number
DB09235
Type
Small Molecule
Groups
Approved, Investigational
Description

Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel. The drug blocks both T-type and 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].

Structure
Thumb
Synonyms
Not Available
External IDs
NZ-105
Product Ingredients
IngredientUNIICASInChI Key
Efonidipine hydrochloride3BR983K69O111011-53-1OXVTXPCIJDYQIS-UHFFFAOYSA-N
International/Other Brands
Landel (Shionogi & Co.) / NZ-105 / Selefodipine
Categories
UNII
40ZTP2T37Q
CAS number
111011-63-3
Weight
Average: 631.666
Monoisotopic: 631.244737574
Chemical Formula
C34H38N3O7P
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

Pharmacology

Indication

For the treatment of hypertension.

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 has a negative chronotropic effect. 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 prevents hypertension-induced renal damage. Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and 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
Human
UVoltage-dependent L-type calcium channel subunit alpha-1CNot AvailableHuman
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). DBZ and DPH exhibit act 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

Peak plasma concentration is achieved at about 1.5 to 3.67 hours after ingestion. Half-life is approximately 4 hours [12].

Clearance
Not Available
Toxicity

Ld50: >5 g/kg in rats, orally [6, 15]. The most common adverse effects are hot flushes, facial flushing, 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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Efonidipine.
AcebutololAcebutolol may increase the hypotensive activities of Efonidipine.
AceclofenacThe therapeutic efficacy of Efonidipine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Efonidipine can be decreased when used in combination with Acemetacin.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Efonidipine.
Acetylsalicylic acidThe therapeutic efficacy of Efonidipine can be decreased when used in combination with Acetylsalicylic acid.
AlbaconazoleThe therapeutic efficacy of Albaconazole can be increased when used in combination with Efonidipine.
AlclofenacThe therapeutic efficacy of Efonidipine can be decreased when used in combination with Alclofenac.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Efonidipine.
AlcuroniumEfonidipine may increase the neuromuscular blocking activities of Alcuronium.
Food Interactions
Not Available

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. [PubMed:12070536]
  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. [PubMed:20558909]
  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. [PubMed:16306803]
  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. [PubMed:20881449]
  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]
External Links
PubChem Compound
119171
PubChem Substance
310265139
ChemSpider
106463
ChEBI
135859
ChEMBL
CHEMBL2074922
Wikipedia
Efonidipine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableRecruitingBasic 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
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Phenylbenzamine / Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Benzylamine / Nitroaromatic compound / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aniline or substituted anilines / Dihydropyridine / Phosphonic acid diester
show 36 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:12070536]
Kind
Protein
Organism
Human
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. [PubMed:12070536]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:22039822]
  2. Pharmacokinetic Interaction between Warfarin and Efonidipine in Rats [Link]

Drug created on October 23, 2015 10:29 / Updated on September 13, 2018 15:58