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Identification
- Summary
Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension.
- Generic Name
- Lacidipine
- DrugBank Accession Number
- DB09236
- Background
Lacidipine is a lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity. Due to its long duration of action, lacidipine does not lead to reflex tachycardia 1. It displays specificity in the vascular smooth muscle, where it acts as an antihypertensive agent to dilate peripheral arterioles and reduce blood pressure. Compared to other dihydropyridine calcium antagonists, lacidipine exhibits a greater antioxidant activity which may confer potentially beneficial antiatherosclerotic effects 4. Lacidipine is a highly lipophilic molecule that interacts with the biological membranes. Through radiotracer analysis, it was determined that lacidipine displays a high membrane partition coefficient leading to accumulation of the drug in the membrane and slow rate of membrane washout 3. When visualized by small-angle X-ray diffraction with angstrom resolution to examine its location within the membranes, lacidipine was found deep within the membrane's hydrocarbon core 3. These results may explain the long clinical half-life of lacidipine 3.
In randomised, well-controlled trials, administration of daily single-dose lacidipine ranging from 2-6 mg demonstrated comparable antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor) 1. It is available as once-daily oral tablets containing 2 or 4 mg of the active compound commonly marketed as Lacipil or Motens. It is not currently FDA-approved.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Lacidipine (DB09236)
- Weight
- Average: 455.551
Monoisotopic: 455.230787787 - Chemical Formula
- C26H33NO6
- Synonyms
- Lacidipine
- Lacidipino
Pharmacology
- Indication
Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors 6.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to manage High blood pressure (hypertension) •••••••••••• ••••••• •••• •••••• Management of High blood pressure (hypertension) •••••••••••• ••••••• •••• •••••• Treatment of High blood pressure (hypertension) •••••••••••• •••••• Treatment of High blood pressure (hypertension) •••••••••••• ••••••• •••••• - Contraindications & Blackbox Warnings
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
acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure 6.
Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers) 6.
- Mechanism of action
By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx 2. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor 5. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel 5.
Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation 4. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques 4.
Target Actions Organism AVoltage-dependent L-type calcium channel antagonistHumans - Absorption
Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing 6. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers 2.
Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver 6.
- Volume of distribution
Not Available
- Protein binding
Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein 6.
- Metabolism
Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity 2.
- Route of elimination
Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine 6.
- Half-life
The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state 6.
- Clearance
Not Available
- Adverse Effects
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There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended 6.
Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively MSDS.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbaloparatide Abaloparatide may increase the hypotensive activities of Lacidipine. Abametapir The serum concentration of Lacidipine can be increased when it is combined with Abametapir. Acarbose The risk or severity of hypoglycemia can be increased when Lacidipine is combined with Acarbose. Acebutolol Acebutolol may increase the hypotensive activities of Lacidipine. Aceclofenac The therapeutic efficacy of Lacidipine can be decreased when used in combination with Aceclofenac. - 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.- International/Other Brands
- Caldine (Boehringer Ingelheim) / Lacimen (GlaxoSmithKline) / Lacipil (GSK) / Motens (Boehringer Ingelheim)
Categories
- ATC Codes
- C08CA09 — Lacidipine
- Drug Categories
- Agents causing hyperkalemia
- Antiarrhythmic agents
- Antihypertensive Agents
- Bradycardia-Causing Agents
- Calcium Channel Blockers
- Calcium-Regulating Hormones and Agents
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Dihydropyridine Derivatives
- Hypotensive Agents
- Membrane Transport Modulators
- Mutagens
- Potential QTc-Prolonging Agents
- Pyridines
- QTc Prolonging Agents
- Selective Calcium Channel Blockers With Mainly Vascular Effects
- Vasodilating Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as cinnamic acid esters. These are compound containing an ester derivative of cinnamic acid.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Cinnamic acids and derivatives
- Sub Class
- Cinnamic acid esters
- Direct Parent
- Cinnamic acid esters
- Alternative Parents
- Tricarboxylic acids and derivatives / Dihydropyridinecarboxylic acids and derivatives / Styrenes / Fatty acid esters / Vinylogous amides / Enoate esters / Amino acids and derivatives / Enamines / Dialkylamines / Azacyclic compounds show 4 more
- Substituents
- Alpha,beta-unsaturated carboxylic ester / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Cinnamic acid ester show 21 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 260080034N
- CAS number
- 103890-78-4
- InChI Key
- GKQPCPXONLDCMU-CCEZHUSRSA-N
- InChI
- InChI=1S/C26H33NO6/c1-8-31-24(29)21-16(3)27-17(4)22(25(30)32-9-2)23(21)19-13-11-10-12-18(19)14-15-20(28)33-26(5,6)7/h10-15,23,27H,8-9H2,1-7H3/b15-14+
- IUPAC Name
- 3,5-diethyl 4-{2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl}-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
- SMILES
- CCOC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C)C(=O)OCC
References
- Synthesis Reference
Lacidipine synthesis: C. Semeraro et al., DE 3529997; eidem, U.S. Patent 4,801,599 (1986, 1989 both to Glaxo).
- General References
- McCormack PL, Wagstaff AJ: Lacidipine: a review of its use in the management of hypertension. Drugs. 2003;63(21):2327-56. [Article]
- Lee CR, Bryson HM: Lacidipine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of hypertension. Drugs. 1994 Aug;48(2):274-96. [Article]
- Herbette LG, Gaviraghi G, Tulenko T, Mason RP: Molecular interaction between lacidipine and biological membranes. J Hypertens Suppl. 1993 Mar;11(1):S13-9. [Article]
- Ishii N, Matsumura T, Shimoda S, Araki E: Anti-atherosclerotic potential of dihydropyridine calcium channel blockers. J Atheroscler Thromb. 2012;19(8):693-704. Epub 2012 May 17. [Article]
- Cerbai E, Giotti A, Mugelli A: Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes. Br J Pharmacol. 1997 Feb;120(4):667-75. doi: 10.1038/sj.bjp.0700951. [Article]
- Lacidipine Summary of Product Characteristics [Link]
- External Links
- KEGG Drug
- D04657
- PubChem Compound
- 5311217
- PubChem Substance
- 310265140
- ChemSpider
- 4470736
- 28382
- ChEBI
- 135737
- ChEMBL
- CHEMBL460291
- ZINC
- ZINC000100015470
- Wikipedia
- Lacidipine
- MSDS
- Download (78.8 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data4 Completed Treatment Essential / Hypertension / Uncomplicated Hypertension 1 somestatus stop reason just information to hide 4 Completed Treatment Hypertension 2 somestatus stop reason just information to hide 4 Completed Treatment Hypertension, Essential Hypertension / Type 2 Diabetes Mellitus 1 somestatus stop reason just information to hide 4 Unknown Status Treatment Hypertension 1 somestatus stop reason just information to hide 3 Completed Treatment Hypertension 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 4 MG Tablet, coated Oral 4 MG Tablet, coated Oral 6 MG Tablet, film coated Oral 2 MG Tablet, film coated Oral 4 MG Tablet, film coated Oral 6 MG Tablet Oral 2.000 mg Tablet, film coated Oral Tablet Oral 6 MG - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00224 mg/mL ALOGPS logP 5.18 ALOGPS logP 4.19 Chemaxon logS -5.3 ALOGPS pKa (Strongest Acidic) 19.47 Chemaxon pKa (Strongest Basic) -6.4 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 90.93 Å2 Chemaxon Rotatable Bond Count 11 Chemaxon Refractivity 129.91 m3·mol-1 Chemaxon Polarizability 49.74 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 232.0009404 predictedDarkChem Lite v0.1.0 [M-H]- 205.64351 predictedDeepCCS 1.0 (2019) [M+H]+ 232.4266404 predictedDarkChem Lite v0.1.0 [M+H]+ 208.03908 predictedDeepCCS 1.0 (2019) [M+Na]+ 232.0216404 predictedDarkChem Lite v0.1.0 [M+Na]+ 214.03215 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein group
- 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
Components:
References
- Cerbai E, Giotti A, Mugelli A: Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes. Br J Pharmacol. 1997 Feb;120(4):667-75. doi: 10.1038/sj.bjp.0700951. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- Antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- Lacidipine Summary of Product Characteristics [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23539.43 Da
References
- Lacidipine Summary of Product Characteristics [Link]
Drug created at October 23, 2015 16:33 / Updated at May 05, 2021 20:31