Acetylcarnitine

Identification

Name
Acetylcarnitine
Accession Number
DB08842
Type
Small Molecule
Groups
Approved, Investigational
Description

Acetylcarnitine is an investigational drug in the United states, Italy, United Kingdom, China, Israel, and Norway, and it is approved in Italy, Portugal, Argentina, Chile, Philippines, Australia, and India. Acetylcarnitine can be synthesized, but it is also naturally found in adequate amounts in healthy humans. In human plasma and tissues, acetylcarnitine is the most predominant acylated ester of carnitine, which is an amino acid derivative that is made in the kidney, liver, and brain from lysine and methionine. The main role of acetylcarnitine is to help transport fatty acids into the mitochondrial matrix where fatty acid metabolism occurs.

Structure
Thumb
Synonyms
  • acetyl-L-carnitine
  • O-acetyl-L-carnitine
  • O-Acetylcarnitine
International/Other Brands
Acilen (IFI (Italy)) / Actigeron (Bago (Chile)) / Branigen (Sigma-Tau (Italy)) / Branitil (OFF (Italy)) / Ceredor (IRBI (Italy)) / Fertilix (Fortbenton (Argentina)) / Lacetilina (Pentafarma (Portugal)) / Laremide (Lafedar (Argentina)) / Levocetile (Korea United (Philippines)) / Maxoza (Sun (India)) / Memorx IQ Plus (Gruppo Medica (Philippines)) / Memovigor (Euro-Pharma (Italy)) / Neurex (Beta (Argentina)) / Neuroactil (Bago (Argentina)) / Nicetile (Sigma-Tau (Italy)) / Normobren (Medosan (Italy)) / Phototrop (Tubilux (Italy)) / Zibren (Sigma-Tau (Italy))
Categories
UNII
6DH1W9VH8Q
CAS number
3040-38-8
Weight
Average: 203.238
Monoisotopic: 203.115758031
Chemical Formula
C9H17NO4
InChI Key
RDHQFKQIGNGIED-MRVPVSSYSA-N
InChI
InChI=1S/C9H17NO4/c1-7(11)14-8(5-9(12)13)6-10(2,3)4/h8H,5-6H2,1-4H3/t8-/m1/s1
IUPAC Name
(3R)-3-(acetyloxy)-4-(trimethylazaniumyl)butanoate
SMILES
CC(=O)O[[email protected]](CC([O-])=O)C[N+](C)(C)C

Pharmacology

Indication

Acetylcarnitine is not approved for any indication in the United states and Canada, but it is approved and indicated in Italy for cerebrovascular disorders, mental function disorders, peripheral nerve disorders, diabetic neuropathy, and nutritional supplementation; Portugal for mental function disorders; Argentina for cerebral vasculopathy, nutritional supplementation, and peripheral neuropathy; Chile for dementia; Philippines for cerebrovascular disorders and mental function disorders; Australia for nutritional supplementation; and India for nutritional supplementation to increase sperm count. Acetylcarnitine also has several potential therapeutic indications for which it is still being investigated: in Norway, acetylcarnitine is in a phase IV trial for prophylactic treatment of migraines; in Italy acetylcarnitine is in a phase II trial for use in patients with type 2 Diabetes Mellitus, a phase III trial for alleviating fatigue in patients with chronic hepatitis C, and for use in patients with Minimal Hepatic Encephalopathy; in the United States acetylcarnitine is in a phase II trial for the neurodegenerative disorder Progressive Supranuclear Palsy, a phase II and III trial for reducing peripheral neuropathy in cancer patients as an adjunct to chemotherapy, a phase I and II trial for treating patients in septic shock, a phase II trial for bipolar depression, a phase II trial to reduce oxidative stress in patients with Sickle Cell disease, a phase I and II trial for chronic fatigue syndrome, and a study for preventing nerve damage in HIV patients; in China acetylcarnitine is in a phase III trial for reducing peripheral neuropathy in cancer patients as an adjunct to chemotherapy; in the United Kingdom acetylcarnitine is being investigated for preventing nerve damage in HIV patients; and in Israel acetylcarnitine is being studied for the treatment of male infertility.

Structured Indications
Not Available
Pharmacodynamics

The complete physiological effects of acetycarnitine are still being studied. What has been discovered so far is that acetylcarinitine has positive effects on mental fatigue, neurodegenerative disorders, cognitive functions, peripheral neuropathy, and sperm motility. Specifically, in one study involving patients with HIV, patients on acetylcarnitine supplementation had increased CD4 cells, decreased lymphocyte apoptosis, improved polyneuropathy and cardiovascular damage, and decreased triglyceride and TNF alpha levels in the blood. Another study showed that acetylcarnitine increased glucose disposal in type 2 diabetic patients through possibly increasing the activity of glycogen synthase.

Mechanism of action

The mechanisms of action of acetylcarnitine have not been fully elucidated, but it seems that the main role of acetylcarnitine is to donate an acetyl group during fatty acid metabolism to help transport fatty acids, such as acetyl CoA, into the mitochondrial matrix where fatty acid metabolism occurs. Additionally several studies have found that separate from its metabolic role, acetylcarnitine has neuromodulatory, neurotrophic, and neuroprotective effects that most likely are involved in its positive effects in neurological diseases. In its role in treating male infertility, acetylcarnitine increases the active movement of sperm cells. One study has also mentioned a role for acetylcarnitine as an antioxidant. The study found that through the receptor, tyrosine kinase A, acetylcarnitine was able to decrease the production of free radicals, peroxidation of lipids, and oxidation of proteins as well as decrease glutathione levels and increase thioredoxin.

Absorption

Acetylcarnitine supplements are absorbed in a similar manner to L-carnitine.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination

Acetylcarnitine is eliminated in a similar manner as L-carnitine. Both of which are eliminated by the kidneys and involve tubular secretion.

Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference

Gu, Heng-da; Shi, Shuang; Yang, Ying; Shi, Zhao-xin; Yu, Zhan-long. Synthesis of acetyl-L-carnitine by direct acylation method. Shenyang Huagong Xueyuan Xuebao (2006), 20(2), 154-155, 160.

General References
  1. Vermeulen RC, Scholte HR: Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar-Apr;66(2):276-82. [PubMed:15039515]
  2. Ilias I, Manoli I, Blackman MR, Gold PW, Alesci S: L-Carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. Mitochondrion. 2004 Jul;4(2-3):163-8. [PubMed:16120381]
  3. Salvioli G, Neri M: L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res. 1994;20(4):169-76. [PubMed:7813389]
  4. Rebouche CJ: Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci. 2004 Nov;1033:30-41. [PubMed:15591001]
  5. Virmani A, Binienda Z: Role of carnitine esters in brain neuropathology. Mol Aspects Med. 2004 Oct-Dec;25(5-6):533-49. [PubMed:15363640]
  6. Giancaterini A, De Gaetano A, Mingrone G, Gniuli D, Liverani E, Capristo E, Greco AV: Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients. Metabolism. 2000 Jun;49(6):704-8. [PubMed:10877193]
  7. Barhwal K, Hota SK, Jain V, Prasad D, Singh SB, Ilavazhagan G: Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation. Neuroscience. 2009 Jun 30;161(2):501-14. doi: 10.1016/j.neuroscience.2009.02.086. Epub 2009 Mar 24. [PubMed:19318118]
  8. Wilson AD, Hart A, Brannstrom T, Wiberg M, Terenghi G: Delayed acetyl-L-carnitine administration and its effect on sensory neuronal rescue after peripheral nerve injury. J Plast Reconstr Aesthet Surg. 2007;60(2):114-8. Epub 2006 Jul 24. [PubMed:17223507]
  9. Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherardi G, Orisio S, Remuzzi G: Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension. 2009 Sep;54(3):567-74. doi: 10.1161/HYPERTENSIONAHA.109.132522. Epub 2009 Jul 20. [PubMed:19620516]
  10. Brayfield, Alison (2014). Martindale : The Complete Drug Reference (38th ed.). Pharmaceutical Press. [ISBN:978-0857111395]
  11. O'Neil, Maryadele J. (2013). The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals (15th ed.). Royal Society of Chemistry, The. [ISBN:978-1849736701]
External Links
KEGG Compound
C02571
PubChem Compound
7045767
PubChem Substance
175427117
ChemSpider
5406074
ChEBI
57589
ChEMBL
CHEMBL1697733
RxList
RxList Drug Page
Wikipedia
Acetylcarnitine
ATC Codes
N06BX12 — Acetylcarnitine
MSDS
Download (39.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentShock, Septic1
2TerminatedPreventionVincristine Induced Neuropathy1
2, 3CompletedTreatmentCarpal Tunnel Syndrome (CTS) / Compression Neuropathy1
3CompletedTreatmentDaily Activity / Quality of Life / Tiredness1
3CompletedTreatmentHypertensive / Type 2 Diabetes Mellitus1
3CompletedTreatmentSensory Peripheral Neuropathy1
3CompletedTreatmentWork Ability / Work Performance / Work Stress1
3TerminatedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
4CompletedTreatmentFatigue in Workers With Chronic C Hepatitis / Tiredness / Work Productivity and Activity Impairment in Workers With Chronic C Hepatitis1
4CompletedTreatmentMigraines1
4RecruitingTreatmentAlzheimer's Disease (AD)1
Not AvailableCompletedNot AvailableHepatic Encephalopathy (Grade 3 of the West Haven Grading Scale)1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Peripheral Nervous System Diseases1
Not AvailableCompletedTreatmentMinimal Hepatic Encephalopathy1
Not AvailableRecruitingTreatmentAntioxidants / Blastocyst / Culture Media / Embryo / Humans / Oxygen1
Not AvailableRecruitingTreatmentFriedreich's Ataxia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)145°CFrom The Merck Index.
water solubilityVery soluble in water and alcohol.From The Merck Index.
Predicted Properties
PropertyValueSource
Water Solubility0.355 mg/mLALOGPS
logP-2.4ALOGPS
logP-4.4ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)4.09ChemAxon
pKa (Strongest Basic)-7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area66.43 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity72.64 m3·mol-1ChemAxon
Polarizability20.89 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9965
Blood Brain Barrier+0.8614
Caco-2 permeable+0.5175
P-glycoprotein substrateNon-substrate0.5593
P-glycoprotein inhibitor INon-inhibitor0.9272
P-glycoprotein inhibitor IINon-inhibitor0.6465
Renal organic cation transporterNon-inhibitor0.916
CYP450 2C9 substrateNon-substrate0.8267
CYP450 2D6 substrateNon-substrate0.8471
CYP450 3A4 substrateSubstrate0.5303
CYP450 1A2 substrateNon-inhibitor0.9367
CYP450 2C9 inhibitorNon-inhibitor0.9236
CYP450 2D6 inhibitorNon-inhibitor0.9355
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8818
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9761
Ames testNon AMES toxic0.8217
CarcinogenicityCarcinogens 0.5207
BiodegradationReady biodegradable0.8743
Rat acute toxicity2.3717 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9728
hERG inhibition (predictor II)Non-inhibitor0.9018
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as acyl carnitines. These are organic compounds containing a fatty acid with the carboxylic acid attached to carnitine through an ester bond.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Fatty acid esters
Direct Parent
Acyl carnitines
Alternative Parents
Dicarboxylic acids and derivatives / Tetraalkylammonium salts / Carboxylic acid salts / Carboxylic acid esters / Carboxylic acids / Organopnictogen compounds / Organic salts / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
show 1 more
Substituents
Acyl-carnitine / Dicarboxylic acid or derivatives / Tetraalkylammonium salt / Quaternary ammonium salt / Carboxylic acid ester / Carboxylic acid salt / Carboxylic acid derivative / Carboxylic acid / Organic nitrogen compound / Organooxygen compound
show 9 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
O-acetylcarnitine, O-acyl-L-carnitine (CHEBI:57589)

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Symporter activity
Specific Function
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cat...
Gene Name
SLC22A5
Uniprot ID
O76082
Uniprot Name
Solute carrier family 22 member 5
Molecular Weight
62751.08 Da
References
  1. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, Shimane M, Tsuji A: Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84. [PubMed:10525100]
  2. Kobayashi D, Tamai I, Sai Y, Yoshida K, Wakayama T, Kido Y, Nezu J, Iseki S, Tsuji A: Transport of carnitine and acetylcarnitine by carnitine/organic cation transporter (OCTN) 2 and OCTN3 into epididymal spermatozoa. Reproduction. 2007 Nov;134(5):651-8. [PubMed:17965255]
Kind
Protein
Organism
Mouse
Pharmacological action
Unknown
Actions
Substrate
General Function
Cation:cation antiporter activity
Specific Function
Sodium-ion independent, medium affinity carnitine transporter. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of ...
Gene Name
Slc22a21
Uniprot ID
Q9WTN6
Uniprot Name
Solute carrier family 22 member 21
Molecular Weight
63320.215 Da
References
  1. Kobayashi D, Tamai I, Sai Y, Yoshida K, Wakayama T, Kido Y, Nezu J, Iseki S, Tsuji A: Transport of carnitine and acetylcarnitine by carnitine/organic cation transporter (OCTN) 2 and OCTN3 into epididymal spermatozoa. Reproduction. 2007 Nov;134(5):651-8. [PubMed:17965255]

Drug created on February 27, 2013 14:42 / Updated on November 09, 2017 04:41