Identification

Name
Calcium levulinate
Accession Number
DB13800
Type
Small Molecule
Groups
Approved, Experimental
Description

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].

Structure
Thumb
Synonyms
  • Calcium laevulate
  • Calcium levulinate anhydrous
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Calcium InjCalcium levulinate (15 mg) + Calcium glycerophosphate (10 mg)LiquidIntramuscular; Intravenous; SubcutaneousKripps Pharmacy Ltd.1981-12-31Not applicableCanada
Categories
UNII
LLQ966USIL
CAS number
591-64-0
Weight
Average: 270.294
Monoisotopic: 270.0416291
Chemical Formula
C10H14CaO6
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

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].

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
UCalmodulin
agonist
Human
UCalsequestrin-1
agonist
Homo sapiens
UCalretinin
agonist
Homo sapiens
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].

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].

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

Interactions

Drug Interactions
DrugInteraction
1alpha-Hydroxyvitamin D5The risk or severity of adverse effects can be increased when Calcium levulinate is combined with 1alpha-Hydroxyvitamin D5.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Calcium levulinate.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Calcium levulinate.
AcetyldigitoxinCalcium levulinate may increase the arrhythmogenic and cardiotoxic activities of Acetyldigitoxin.
AcetyldigoxinCalcium levulinate may increase the arrhythmogenic and cardiotoxic activities of Acetyldigoxin.
AgmatineThe therapeutic efficacy of Agmatine can be decreased when used in combination with Calcium levulinate.
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 Calcium levulinate is combined with Alfacalcidol.
AmiodaroneThe therapeutic efficacy of Amiodarone can be decreased when used in combination with Calcium levulinate.
AmlodipineThe therapeutic efficacy of Amlodipine can be decreased when used in combination with Calcium levulinate.
Food Interactions
Not Available

References

General References
  1. Burckhardt P: Calcium revisited: part I. Bonekey Rep. 2013 Oct 16;2:433. doi: 10.1038/bonekey.2013.167. [PubMed:24422133]
  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. [PubMed:22453954]
  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]
External Links
KEGG Compound
C18380
ChemSpider
11090
ChEBI
81717
ATC Codes
A12AA30 — Calcium laevulate
MSDS
Download (47.1 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidIntramuscular; Intravenous; Subcutaneous
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

Taxonomy

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
Gamma-keto acid / Short-chain keto acid / Ketone / Carboxylic acid salt / Organic calcium salt / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic oxygen compound / Organic oxide
Molecular Framework
Not Available
External Descriptors
organic molecular entity (CHEBI:81717)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Titin binding
Specific Function
Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number...
Gene Name
CALM1
Uniprot ID
P0DP23
Uniprot Name
Calmodulin
Molecular Weight
16837.47 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. [PubMed:22453954]
Kind
Protein
Organism
Homo sapiens
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. 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. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction.
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. [PubMed:22453954]
Kind
Protein
Organism
Homo sapiens
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. [PubMed:22453954]

Drug created on June 23, 2017 14:48 / Updated on November 02, 2018 07:46