Barnidipine

Identification

Summary

Barnidipine is a calcium channel blocker used to treat various forms of hypertension.

Generic Name
Barnidipine
DrugBank Accession Number
DB09227
Background

Barnidipine is a long-acting novel calcium antagonist that belongs to the dihydropyridine (DHP) group of calcium channel blockers. Used in the treatment of hypertension, barnidipine displays high affinity for the calcium channels of the smooth muscle cells in the vascular wall 8 and selectivity against cardiovascular L-type calcium channels 1. Barnidipine contains two chiral centres thus can have four possible enantiomers. The active component is composed of a single optical isomer (3'S, 4S configuration), which is the most potent and longest-acting of the four enantiomers 3. Compared to several other calcium antagonists which are racemates, the barnidipine compound consisting of a single enantiomer may offer a high degree of pharmacological selectivity 3.

According to a dose-ranging, multicentre, placebo-controlled, double-blind study in patients with mild to moderate hypertension, the antihypertensive response from barnidipine treatment was maintained after a 1-year and 2-year follow-up period in 91% of the patients who had an initial response to the drug 1. In two European multicentre randomized, double-blind trials, barnidipine was shown to possess equivalent antihypertensive efficacy to amlodipine and nitrendipine, but produced fewer class-specific side-effects 4. It also demonstrated clinical efficacy which is similar to that of atenolol, enalapril and hydrochlorothiazide 1.

It is available in modified-release oral tablets under the brand name Vasexten to be taken once daily in the morning. Barnidipine has a gradual onset of action and is shown to be well tolerated in patients. It does not produce reflex tachycardia 1.

Type
Small Molecule
Groups
Experimental
Structure
Weight
Average: 491.544
Monoisotopic: 491.205635666
Chemical Formula
C27H29N3O6
Synonyms
  • Barnidipine
  • Barnidipino
  • Mepirodipine

Pharmacology

Indication

Indicated for the treatment of mild to moderate essential hypertension and management of chronic stable angina.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofArterial hypertension•••••••••••••••••••• •••••••• •••••••
Management ofEssential hypertension ( mild to moderate)••••••••••••
Treatment ofRenovascular hypertension•••••••••••••••••••
Treatment ofRenal parenchymal hypertension•••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Barnidipine reduces peripheral resistance and lowers blood pressure. The chronic use of the drug is not reported to lead to an increase in basic heart frequency. The antihypertensive effects of barnidipine are reported to remain during the entire 24-hour dose interval. Barnidipine does not exert any negative effect on serum lipids profile, glucose level or blood electrolytes 8.

Mechanism of action

Barnidipine is a lipophilic 1,4-dihydropyridine calcium antagonist that is characterized by a slow onset of action and a strong and long-lasting binding to the L-type calcium channels 8. It displays high affinity for the channels expressed in the smooth muscle cells in the vascular wall. Its main mechanism of action arises from the reduction of peripheral vascular resistance secondary to its vasodilatory actions.

Calcium ion influx via L-subtype ‘voltage-operated’ channels in the excitable membranes of the smooth muscle cells promotes the formation of calcium-dependent formation of cross-bridges between myosin and actin which are the two major contractile proteins that drive contraction. By blocking the L-type 'voltage-dependent' calcium channels, barnidipine selectively blocks the calcium ion influx in the smooth muscle cells and inhibits the activation of contractile proteins 3. It is suggested that barnidipine displays a high affinity to the inactivated state of the channel 5. Like other dihydropyridine calcium antagonists, barnidipine is predicted to interact with the alpha 1-C subunit of the L-type calcium channels. Alpha 1-C subunit of the channel is predicted to reside within the bilayer or channel pore at a location closer to the extracellular rather than the intracellular face of the membrane 6,7. Its lipophilicity is likely a reason why barnidipine displays a slow onset and long duration of action. Being a highly lipophilic molecule with an octanol/water partition coefficient of 2000, barnidipine is expected to accumulate in the cell membrane and consequently, gains access to its target receptor in a slow manner 3.

TargetActionsOrganism
AVoltage-dependent L-type calcium channel subunit alpha-1C
antagonist
Humans
UVoltage-dependent T-type calcium channel subunit alpha-1G
antagonist
inhibitor
Humans
UVoltage-dependent T-type calcium channel subunit alpha-1H
antagonist
inhibitor
Humans
Absorption

Following a single, modified-release dose of 10mg barnidipine, the peak plasma concentration was approximately 0.48 µg/L and the area under the curve (AUC) was 2.85 µg/Lxh 1. The peak plasma concentrations are reached within 5 to 6 hours after oral administration of 20mg barnidipine. While the plasma concentrations of the drug may vary between individuals, the absolute bioavailability of the barnidipine is approximately 1.1% due to extensive first-pass hepatic metabolism 8. After repeated administration of 20mg barnidipine to healthy individuals, the concomitant intake of food did not have a statistically significant effect on the AUC, Cmax or half-life of the drug 8.

Volume of distribution

After administration of single oral doses of radiolabelled barnidipine in rats, levels of radioactivity were found to be higher in the kidney, liver and gastrointestinal tract than in plasma, whereas the brain showed the lowest level of radioactivity. The drug was also detectable in the breast milk 1.

Protein binding

In vitro binding of barnidipine with plasma proteins was between 92.4 and 98.9%, and was mainly with albumin 1. Barnidipine binds at the rate of 26-32% to human erythrocytes. In addition to serum albumin, barnidipine also binds to α1 acid glycoprotein and high density lipoproteins. To a much lesser extent, binding to γ-globulin takes place 8.

Metabolism

Barnidipine is expected to undergo hepatic metabolism. The primary metabolism of barnidipine involves the oxidation of the 1,4-dihydropyridine ring and hydrolysis of the methyl ester. Secondary metabolism involves N-debenzylization of the side chain, hydrolysis of the N-benzylpyrrolidine ester, and reduction of the nitro group 2. Both the primary and secondary metabolic pathways are mediated by the CYP3A isoenzyme family and the metabolites formed are pharmacologically inactive 1,8.

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Route of elimination

Barnidipine and its metabolites are metabolized into feces (60%), urine (40%) and breath (1%) 8. Following a single dose administration of barnidipine ranging from 5 to 20mg in healthy volunteers, urinary excretion of unchanged drug was negligible (≤0.003% of an administered dose) 1.

Half-life

In a two-compartment analytical model, the median terminal elimination half life of barnidipine was 20 hours after repeated administration 8.

Clearance

Not Available

Adverse Effects
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Toxicity

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 8. Oral LD50 in rat and mouse are 105mg/kg and 108mg/kg, respectively MSDS.

In general, the clinical symptoms from overdose of calcium antagonists appear within 30 to 60 minutes of after administration of a dose five to ten times higher than the therapeutic dose. Possible symptoms that may develop include hypotension, electrophysiological effects (sinus bradycardia, prolonged AV conduction, second and third degree AV block, tachycardia), effects on the central nervous system (drowsiness, confusion and, rarely, convulsions), gastrointestinal symptoms (nausea and vomiting) and metabolic effects (hyperglycaemia) 8.

In the case of intoxication, symptomatic treatment and continuous ECG monitoring in the clinical setting are recommended. In the case of overdose, gastric lavage is strongly recommended. An intravenous (dosage 0.2 ml/kg body weight) injection of calcium (preferably 10 ml of a calcium chloride solution of 10%) should be given over a period of 5 minutes, up to a total dose of 10 ml 10%. Contractility of the myocardium, sinus rhythm and atrioventricular conduction will thus be improved. The treatment can be repeated every 15 to 20 minutes (up to a total of 4 doses) based on the patient’s response. Calcium levels should be checked 8.

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
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Barnidipine.
AbaloparatideThe risk or severity of adverse effects can be increased when Abaloparatide is combined with Barnidipine.
AbametapirThe serum concentration of Barnidipine can be increased when it is combined with Abametapir.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Barnidipine.
AbirateroneThe metabolism of Barnidipine can be decreased when combined with Abiraterone.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Barnidipine hydrochloride7LZ6R3AEM1104757-53-1XEMPUKIZUCIZEY-YSCHMLPRSA-N

Categories

ATC Codes
C08CA12 — Barnidipine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Dihydropyridinecarboxylic acids and derivatives
Alternative Parents
Nitrobenzenes / Phenylmethylamines / Benzylamines / Nitroaromatic compounds / Aralkylamines / Dicarboxylic acids and derivatives / N-alkylpyrrolidines / Vinylogous amides / Enoate esters / Methyl esters
show 12 more
Substituents
Allyl-type 1,3-dipolar organic compound / Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Benzylamine / C-nitro compound
show 31 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
2VBY96ASWJ
CAS number
104713-75-9
InChI Key
VXMOONUMYLCFJD-DHLKQENFSA-N
InChI
InChI=1S/C27H29N3O6/c1-17-23(26(31)35-3)25(20-10-7-11-21(14-20)30(33)34)24(18(2)28-17)27(32)36-22-12-13-29(16-22)15-19-8-5-4-6-9-19/h4-11,14,22,25,28H,12-13,15-16H2,1-3H3/t22-,25-/m0/s1
IUPAC Name
3-(3S)-1-benzylpyrrolidin-3-yl 5-methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(C)NC(C)=C([C@H]1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)O[C@H]1CCN(CC2=CC=CC=C2)C1

References

General References
  1. Malhotra HS, Plosker GL: Barnidipine. Drugs. 2001;61(7):989-96; discussion 997-8. [Article]
  2. Teramura T, Watanabe T, Higuchi S, Hashimoto K: Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation. Xenobiotica. 1997 Feb;27(2):203-16. doi: 10.1080/004982597240695 . [Article]
  3. van Zwieten PA: Pharmacological profile of barnidipine: a single optical isomer dihydropyridine calcium antagonist. Blood Press Suppl. 1998;1:5-8. [Article]
  4. Spieker C: Efficacy and tolerability of once-daily barnidipine in the clinical management of patients with mild to moderate essential hypertension. Blood Press Suppl. 1998;1:15-21. [Article]
  5. Wegener JW, Meyrer H, Rupp J, Nawrath H: Barnidipine block of L-type Ca(2+) channel currents in rat ventricular cardiomyocytes. Br J Pharmacol. 2000 Aug;130(8):2015-23. doi: 10.1038/sj.bjp.0703514. [Article]
  6. Kwan YW, Bangalore R, Lakitsh M, Glossmann H, Kass RS: Inhibition of cardiac L-type calcium channels by quaternary amlodipine: implications for pharmacokinetics and access to dihydropyridine binding site. J Mol Cell Cardiol. 1995 Jan;27(1):253-62. [Article]
  7. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [Article]
  8. Vasexten (barnidipine hydrochloride modified release capsules) Summary of Product Characteristics [Link]
PubChem Compound
443869
PubChem Substance
310265132
ChemSpider
391959
BindingDB
50088384
RxNav
39879
ChEBI
135793
ChEMBL
CHEMBL2103761
ZINC
ZINC000100011067
Wikipedia
Barnidipine
MSDS
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Clinical Trials

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Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule10 MG
Capsule20 MG
Capsule, delayed releaseOral10 MG
Capsule, delayed releaseOral20 MG
Capsule, delayed releaseOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)226MSDS
boiling point (°C)614.5MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.004 mg/mLALOGPS
logP4.12ALOGPS
logP3.51Chemaxon
logS-5.1ALOGPS
pKa (Strongest Acidic)19.47Chemaxon
pKa (Strongest Basic)7.91Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area111.01 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity136.36 m3·mol-1Chemaxon
Polarizability51.03 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-209.97672
predicted
DeepCCS 1.0 (2019)
[M+H]+211.8016
predicted
DeepCCS 1.0 (2019)
[M+Na]+217.40742
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:11741969, PubMed:12176756, PubMed:12181424, PubMed:15454078, PubMed:15863612, PubMed:16299511, PubMed:17071743, PubMed:17224476, PubMed:20953164, PubMed:23677916, PubMed:24728418, PubMed:26253506, PubMed:27218670, PubMed:29078335, PubMed:29742403, PubMed:30023270, PubMed:30172029, PubMed:34163037, PubMed:7737988, PubMed:8099908, PubMed:8392192, PubMed:9013606, PubMed:9087614, PubMed:9607315). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm (PubMed:15454078, PubMed:15863612, PubMed:17224476, PubMed:24728418, PubMed:26253506). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (PubMed:28119464). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable)
Specific Function
alpha-actinin binding
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. Kwan YW, Bangalore R, Lakitsh M, Glossmann H, Kass RS: Inhibition of cardiac L-type calcium channels by quaternary amlodipine: implications for pharmacokinetics and access to dihydropyridine binding site. J Mol Cell Cardiol. 1995 Jan;27(1):253-62. [Article]
  2. Tikhonov DB, Zhorov BS: Structural model for dihydropyridine binding to L-type calcium channels. J Biol Chem. 2009 Jul 10;284(28):19006-17. doi: 10.1074/jbc.M109.011296. Epub 2009 May 5. [Article]
  3. Yamaguchi S, Okamura Y, Nagao T, Adachi-Akahane S: Serine residue in the IIIS5-S6 linker of the L-type Ca2+ channel alpha 1C subunit is the critical determinant of the action of dihydropyridine Ca2+ channel agonists. J Biol Chem. 2000 Dec 29;275(52):41504-11. doi: 10.1074/jbc.M007165200. [Article]
  4. Vasexten (barnidipine hydrochloride modified release capsules) Summary of Product Characteristics [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
Inhibitor
General 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, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.
Specific Function
high voltage-gated calcium channel activity
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
Unknown
Actions
Antagonist
Inhibitor
General Function
Voltage-sensitive calcium channel that gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group. A particularity of this type of channel is an opening at quite negative potentials, and a voltage-dependent inactivation (PubMed:27149520, PubMed:9670923, PubMed:9930755). T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle (Probable). They may also be involved in the modulation of firing patterns of neurons (PubMed:15048902). In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia (PubMed:25907736, PubMed:27729216)
Specific Function
high voltage-gated calcium channel activity
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
No
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Liau CS: Barnidipine: a new calcium channel blocker for hypertension treatment. Expert Rev Cardiovasc Ther. 2005 Mar;3(2):207-13. doi: 10.1586/14779072.3.2.207. [Article]
  2. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T: Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol. 2000 Feb-Mar;55(11-12):843-52. [Article]

Drug created at October 22, 2015 20:52 / Updated at February 03, 2022 21:01