Calcium levulinate

Overview

DrugBank ID
DB13800
Type
Small Molecule
US Approved
NO
Other Approved
YES
Clinical Trials
Phase 0
0
Phase 1
0
Phase 2
0
Phase 3
0
Phase 4
0

Identification

Generic Name
Calcium levulinate
DrugBank Accession Number
DB13800
Background

The relatively new calcium levulinate is produced from a direct reaction between L- or levulinic acid levulose and calcium hydroxide 3. The resultant calcium levulinate formulation, when used as a calcium supplement, possesses a high calcium content that is observed to be 14.8% higher than the content typically found in calcium lactate 3. This formulation is considered a low molecular weight organic calcium ion type that is easily absorbed through the intestinal wall 3.

This new application of calcium is intended for use as a food fortifier, to fortify foods like sauces, condiments, beer, beverages, soft drinks, milk and milk products, soy milk and soy products with calcium nutrition 3. Calcium levulinate can be used alone, or with calcium lactate, calcium chloride, and other compounds, either for pharmaceutical tablets, capsules, or injections preparation 3.

Type
Small Molecule
Groups
Approved, Experimental
Structure
Weight
Average: 270.294
Monoisotopic: 270.0416291
Chemical Formula
C10H14CaO6
Synonyms
  • Calcium laevulate
  • Calcium levulinate anhydrous

Pharmacology

Indication

This new application of calcium is intended for use as a food fortifier, to fortify foods like sauces, condiments, beer, beverages, soft drinks, milk and milk products, soy milk and soy products with calcium nutrition 3. Calcium levulinate can be used alone, or with calcium lactate, calcium chloride, and other compounds, either for pharmaceutical tablets, capsules, or injections preparation 3. In essence, calcium levulinate is ultimately a relatively new calcium supplementation option 5.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatHypocalcemiaCombination Product in combination with: Calcium gluconate (DB11126)•••••••••••••••••••••• •••••••••• ••••••••• ••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The relatively new calcium levulinate is produced from a direct reaction between L- or levulinic acid levulose and calcium hydroxide 3. The resultant calcium levulinate formulation, when used as a calcium supplement, possesses a high calcium content that is observed to be 14.8% higher than the content typically found in calcium lactate 3. Moreover, this formulation also demonstrates a high solubility of more than 30% at 25℃ 3. Furthermore, the calcium levulinate is believed to be non-toxic and non-allergic, making it especially suitable for injection or infusion administrations 3. Additionally, this levulinate formulation is reported as having a good taste, little irritation with a pH value of 7, and good stability such that no precipitation or deterioration occurs during use 3. Finally, this calcium levulinate formulation is also believed to have good compatibility with calcium lactate, calcium chloride, and other material complexes which allows the formulation to also complex effectively with a diverse variety of foodstuffs and pharmaceutical dosage forms 3.

Mechanism of action

Much like most calcium supplements, once calcium levulinate dissociates in the body after administration, absorption of the supplemental calcium ions across the intestinal wall serves to enhance calcium stores in the body 3,5,1.

Regardless, levulinic acid (LA) is a commonly used chemical with one carbonyl group, one carboxyl group, and alpha-H comprised in its inner structure, which belongs to short-chain and non-volatile fatty acids 5. Moreover, the carbon-oxygen double bond from LA's carbonyl group possesses a strong polarity, where the oxygen atom has a stronger electron attracting ability compared to the carbon atom, such that the pi electron will ultimately transfer into the greater electronegative oxygen, therefore resulting in the formation of a positive charge center in the carbon atom 5. The electrophilic center of the carbon atom subsequently plays a critical role when the carbonyl group performs chemical reactions 5. Owing to the relatively strong electron receptor effect of the oxygen atom of the carbonyl group, LA has higher dissociation constants than a common saturated acid, which allows it to possess a stronger corresponding acidity 5. Furthermore, LA can be isomerized into the enol-isomer, owing to the presence of the carbonyl group 5. The chemical structure of LA consequently has several highly active sites, which facilitates it being used as a chemical platform for preparing many other chemical products 5. For example, the special structure of LA allows various kinds of products to be generated by way of esterification, halogenation, hydrogenation, oxy-dehydrogenation, and/or condensation, among many other methods 5.

TargetActionsOrganism
UCalsequestrin-1
agonist
Humans
UCalretinin
agonist
Humans
UCalmodulin
agonist
Humans
Absorption

General calcium absorption occurs primarily in the duodenum by an active transcellular and saturable system, which is stimulated and regulated by 1,25(OH)2D,25 and through a passive and vitamin D-independent paracellular transport in the jejunum and ileum, and even in the colon - where absorption is only about 4% even when the intake is high 1. Ultimately, calcium absorption depends mainly on the amount of intake - in general, absorption increases at lower intakes and decreases at high intakes 1.

Readily accessible data regarding the specific absorption of calcium levulinate is not available although the formulation is considered a low molecular weight organic calcium ion type that is easily absorbed through the intestinal wall 3.

Volume of distribution

99% of the body's calcium supply is stored in the bones and teeth where it supports their structure and function 6. Elsewhere, 1% or less of this calcium supply is used for essential metabolic functions like vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion, among other activities 6.

Protein binding

Readily accessible data regarding the protein binding of calcium levulinate is not available, although many different calcium-binding proteins exist, with different cellular and tissue distribution and involvement in specific biological function 2. Some of these proteins include calmodulin, calsequestrin, calretinin, and calcineurin, among others 2.

Metabolism

Although calcium levulinate dissociates into absorbable calcium ion once it is administered into the body, there have been studies to suggest that the levulinate component is metabolized to 4-hydroxypentanoate - a compound that has similar pharmacologic effects as but at a lower level of potency than the 'date rape' drug gamma-hydroxybutyrate 8.

Route of elimination

Calcium leaves the body mainly in urine and feces, but also in other body tissues and fluids, like sweat 7. Overall, a typical daily calcium loss for a healthy adult man or woman via renal excretion is approximately 5 mmol/day 7 while endogenous fecal calcium losses are about 2.1 mg/kg per day in adults and about 1.4 mg/kg per day in children 7.

Half-life

Readily accessible data regarding the half-life of calcium levulinate is not available.

Clearance

Despite inter-individual differences, general clinical lab tests list some reference calcium clearance values as being considered a 'normal range', like urine calcium as approximately < 250 mg/24 h 9.

Adverse Effects
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Toxicity

Overdosage with calcium resulting in excessively high levels of calcium in the blood known as hypercalcemia can cause renal insufficiency, vascular and soft tissue calcification, hypercalciuria, and kidney stones 6.

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
AcebutololThe therapeutic efficacy of Acebutolol can be decreased when used in combination with Calcium levulinate.
AcetyldigitoxinCalcium levulinate may increase the arrhythmogenic and cardiotoxic activities of Acetyldigitoxin.
Alendronic acidThe serum concentration of Alendronic acid can be decreased when it is combined with Calcium levulinate.
AlfacalcidolThe risk or severity of adverse effects can be increased when Alfacalcidol is combined with Calcium levulinate.
AmiodaroneThe therapeutic efficacy of Amiodarone can be decreased when used in combination with Calcium levulinate.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Calcium levulinate dihydrateT6133SO7815743-49-7WQFDRFDIWAMOPA-UHFFFAOYSA-L
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
CALCİLES 225 MG+572 MG/10 ML ENJEKSİYONLUK ÇÖZELTİ, 5 ADETCalcium levulinate (572 mg/10mL) + Calcium gluconate monohydrate (225 mg/10mL)Injection, solutionParenteralVEM İLAÇ SAN. VE TİC. A.Ş.2018-03-14Not applicableTurkey flag
CALCIO AL 10% AMPOLLASCalcium levulinate (400 mg) + Calcium gluconate monohydrate (600 mg)SolutionIntravenousLABORATORIOS RYAN DE COLOMBIA S.A.S2008-10-07Not applicableColombia flag
CALCİOSEL 225 mg + 572 mg / 10 mL ENJEKSIYONLUK ÇÖZELTICalcium levulinate dihydrate (572 mg/10ml) + Calcium gluconate monohydrate (225 mg/10ml)InjectionIntramuscularHAVER FARMA İLAÇ A.Ş.2016-04-20Not applicableTurkey flag
Calcium InjCalcium levulinate (15 mg) + Calcium glycerophosphate (10 mg)LiquidIntramuscular; Intravenous; SubcutaneousKripps Pharmacy Ltd.1981-12-31Not applicableCanada flag
CALCIUM PICKEN %10 ENJEKSİYONLUK ÇÖZELTİ 100 AMPULCalcium levulinate dihydrate (572 mg) + Calcium gluconate monohydrate (225 mg)InjectionIntramuscularADEKA İLAÇ SAN. VE TİC. A.Ş.2020-08-14Not applicableTurkey flag

Categories

ATC Codes
A12AA30 — Calcium laevulate
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as gamma-keto acids and derivatives. These are organic compounds containing an aldehyde substituted with a keto group on the C4 carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Keto acids and derivatives
Sub Class
Gamma-keto acids and derivatives
Direct Parent
Gamma-keto acids and derivatives
Alternative Parents
Short-chain keto acids and derivatives / Ketones / Carboxylic acid salts / Organic calcium salts / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives
Substituents
Aliphatic acyclic compound / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Carboxylic acid salt / Gamma-keto acid / Hydrocarbon derivative / Ketone / Monocarboxylic acid or derivatives / Organic calcium salt
Molecular Framework
Not Available
External Descriptors
organic molecular entity (CHEBI:81717)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
LLQ966USIL
CAS number
591-64-0
InChI Key
APKDPOQXVKRLEP-UHFFFAOYSA-L
InChI
InChI=1S/2C5H8O3.Ca/c2*1-4(6)2-3-5(7)8;/h2*2-3H2,1H3,(H,7,8);/q;;+2/p-2
IUPAC Name
calcium bis(4-oxopentanoate)
SMILES
[Ca++].CC(=O)CCC([O-])=O.CC(=O)CCC([O-])=O

References

General References
  1. Burckhardt P: Calcium revisited: part I. Bonekey Rep. 2013 Oct 16;2:433. doi: 10.1038/bonekey.2013.167. [Article]
  2. Yanez M, Gil-Longo J, Campos-Toimil M: Calcium binding proteins. Adv Exp Med Biol. 2012;740:461-82. doi: 10.1007/978-94-007-2888-2_19. [Article]
  3. Preparing process and application of calcium lévulinate [Link]
  4. Energy densification of levulinic acid by thermal deoxygenation [Link]
  5. Advances in the Catalytic Production of Valuable Levulinic Acid Derivatives [Link]
  6. National Institutes of Health: Calcium Fact Sheet [Link]
  7. Dietary Reference Intakes for Calcium and Vitamin D [Link]
  8. Chemical Research in Toxicology: Levulinate - Potentially Toxic Pro-Drug of Abuse [File]
  9. Clinical Laboratory Tests Reference Values (from http://www.royalcollege.ca/rcsite/documents/credential-exams/clinical-lab-tests-reference-values-e.pdf) [File]
KEGG Compound
C18380
ChemSpider
11090
RxNav
47624
ChEBI
81717
MSDS
Download (47.1 KB)

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionParenteral
SolutionIntravenous
LiquidIntramuscular; Intravenous; Subcutaneous
InjectionIntramuscular
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.82 mg/mLALOGPS
logP0.76ALOGPS
logP-0.069Chemaxon
logS-2.2ALOGPS
pKa (Strongest Acidic)4.32Chemaxon
pKa (Strongest Basic)-7.3Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area57.2 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity37.93 m3·mol-1Chemaxon
Polarizability10.8 Å3Chemaxon
Number of Rings0Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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]-144.71559
predicted
DeepCCS 1.0 (2019)
[M+H]+147.0772
predicted
DeepCCS 1.0 (2019)
[M+Na]+153.16689
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:28895244). Calcium ions are bound by clusters of acidic residues at the protein surface, often at the interface between subunits. Can bind around 80 Ca(2+) ions (PubMed:28895244). Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction. Negatively regulates store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316)
Specific Function
calcium ion binding
Gene Name
CASQ1
Uniprot ID
P31415
Uniprot Name
Calsequestrin-1
Molecular Weight
45159.635 Da
References
  1. Yanez M, Gil-Longo J, Campos-Toimil M: Calcium binding proteins. Adv Exp Med Biol. 2012;740:461-82. doi: 10.1007/978-94-007-2888-2_19. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Calretinin is a calcium-binding protein which is abundant in auditory neurons
Specific Function
calcium ion binding
Gene Name
CALB2
Uniprot ID
P22676
Uniprot Name
Calretinin
Molecular Weight
31539.62 Da
References
  1. Yanez M, Gil-Longo J, Campos-Toimil M: Calcium binding proteins. Adv Exp Med Biol. 2012;740:461-82. doi: 10.1007/978-94-007-2888-2_19. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Is a regulator of voltage-dependent L-type calcium channels (PubMed:31454269). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696). Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding (PubMed:25441029). Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (PubMed:28890335)
Specific Function
adenylate cyclase activator activity

Components:
References
  1. Yanez M, Gil-Longo J, Campos-Toimil M: Calcium binding proteins. Adv Exp Med Biol. 2012;740:461-82. doi: 10.1007/978-94-007-2888-2_19. [Article]

Drug created at June 23, 2017 20:48 / Updated at November 05, 2024 05:15