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| Clinical data | |
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| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| Routes of administration | Oral,intravenous |
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| Pharmacokinetic data | |
| Bioavailability | <10% |
| Protein binding | None |
| Metabolism | slightly[clarification needed] |
| Excretion | Urine (>95%) |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.006.343 |
| Chemical and physical data | |
| Formula | C7H15NO3 |
| Molar mass | 161.201 g·mol−1 |
| 3D model (JSmol) | |
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Carnitine is aquaternary ammonium compound involved inmetabolism in most mammals, plants, and some bacteria.[1][2][3][4] In support of energy metabolism, carnitine transportslong-chain fatty acids from the cytosol intomitochondria to beoxidized for free energy production, and also participates in removing products of metabolism from cells.[3] Given its key metabolic roles, carnitine is concentrated in tissues likeskeletal andcardiac muscle that metabolize fatty acids as an energy source.[3] Generally individuals, including strictvegetarians, synthesize enough L-carnitinein vivo.[1]
Carnitine exists as one of twostereoisomers: the twoenantiomersd-carnitine (S-(+)-) andl-carnitine (R-(−)-).[5] Both are biologically active, but onlyl-carnitine naturally occurs in animals, andd-carnitine is toxic as it inhibits the activity of thel-form.[6] At room temperature, pure carnitine is a whiteish powder, and a water-solublezwitterion with relatively low toxicity. Derived from amino acids,[7] carnitine was firstextracted from meat extracts in 1905, leading to its name from Latin, "caro/carnis" or flesh.[2]
Some individuals withgenetic or medical disorders (such as preterm infants) cannot make enough carnitine, requiring dietary supplementation.[1][3][4] Despite common carnitine supplement consumption amongathletes for improved exercise performance or recovery, there is insufficienthigh-quality clinical evidence to indicate it provides any benefit.[3][4]
The primary biological functions of carnitine in humans include the following:[8]
Carnitine is azwitterion, meaning it has both positive and negative charges in its structure. In an aqueous solution, L-carnitine is freely soluble and its ionizable groups, COO− and N+(CH3)3, are over 90%dissociated at physiological pH (~7.4) for humans.[9]
As an example of normal biosynthesis of carnitine in humans, a 70-kilogram (150 lb) person would produce 11–34 mg of carnitine per day.[1] Adults eating mixed diets ofred meat and otheranimal products ingest some 60–180 mg of carnitine per day, while vegans consume about 10–12 mg per day.[3] Most (54–86%) carnitine obtained from the diet is absorbed in thesmall intestine before entering the blood.[3] The total body content of carnitine is about 20 grams (0.71 oz) in a person weighing 70 kilograms (150 lb), with nearly all of it contained within skeletal muscle cells.[3] Carnitine metabolizes at rates of about 400 μmol (65 mg) per day, an amount less than 1% of total body stores.[1]
Manyeukaryotes have the ability to synthesize carnitine, including humans.[1][3] Humans synthesize carnitine from the substrateTML (6-N-trimethyllysine), which is in turn derived from themethylation of the amino acidlysine.[1] TML is then hydroxylated into hydroxytrimethyllysine (HTML) bytrimethyllysine dioxygenase (TMLD), requiring the presence ofascorbic acid and iron. HTML is then cleaved by HTML aldolase (HTMLA, apyridoxal phosphate requiring enzyme), yielding 4-trimethylaminobutyraldehyde (TMABA) andglycine. TMABA is thendehydrogenated into gamma-butyrobetaine in an NAD+-dependent reaction, catalyzed by TMABA dehydrogenase.[1] Gamma-butyrobetaine is then hydroxylated bygamma butyrobetaine hydroxylase (azinc binding enzyme[10]) intol-carnitine, requiring iron in the form ofFe2+.[1][11]
Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported bycarnitine palmitoyltransferase I andcarnitine palmitoyltransferase II.[12]
Carnitine plays a role in stabilizingacetyl-CoA andcoenzyme A levels through the ability to receive or give an acetyl group.[1]
The tissue distribution of carnitine-biosynthetic enzymes in humans indicates TMLD to be active in the liver, heart, muscle, brain and highest in the kidneys.[1] HTMLA activity is found primarily in the liver. The rate of TMABA oxidation is greatest in the liver, with considerable activity also in the kidneys.[1]
The free-floatingfatty acids, released fromadipose tissues to the blood, bind to carrier protein molecules known asserum albumin that carry the fatty acids to thecytoplasm of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. Before the target cells can use the fatty acids for ATP production andβ oxidation, the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported intomitochondrial matrix of the cells in three enzymatic reactions of the carnitine shuttle.[13]
The first reaction of the carnitine shuttle is a two-step process catalyzed by a family ofisozymes ofacyl-CoA synthetase that are found in the outer mitochondrial membrane, where they promote the activation of fatty acids by forming athioester bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.[13]
In the first step of the reaction, acyl-CoA synthetase catalyzes the transfer ofadenosine monophosphate group (AMP) from an ATP molecule onto the fatty acid generating a fatty acyl–adenylate intermediate and a pyrophosphate group (PPi). Thepyrophosphate, formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecules of Pi by inorganic pyrophosphatase. This reaction is highly exergonic which drives the activation reaction forward and makes it more favorable. In the second step, thethiol group of a cytosoliccoenzyme A attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA.[13]
In the second reaction, acyl-CoA is transiently attached to the hydroxyl group of carnitine to form fatty acylcarnitine. This transesterification is catalyzed by an enzyme found in the outer membrane of the mitochondria known as carnitine acyltransferase 1 (also called carnitine palmitoyltransferase 1, CPT1).[13]
The fatty acylcarnitine ester formed then diffuses across the intermembrane space and enters the matrix byfacilitated diffusion throughcarnitine-acylcarnitine translocase (CACT) located on the inner mitochondrial membrane. Thisantiporter returns one molecule of carnitine from the matrix to theintermembrane space for every one molecule of fatty acyl–carnitine that moves into the matrix.[13]
In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred from fatty acyl-carnitine to coenzyme A, regenerating fatty acyl–CoA and a free carnitine molecule. This reaction takes place in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also called carnitine palmitoyltransferase 2, CPT2), which is located on the inner face of the inner mitochondrial membrane. The carnitine molecule formed is then shuttled back into the intermembrane space by the same cotransporter (CACT) while the fatty acyl-CoA entersβ-oxidation.[13]
The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation.[13]
The liver starts actively makingtriglycerides from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration ofmalonyl-CoA, the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix forβ oxidation. This inhibition prevents fatty acid breakdown while synthesis occurs.[13]
Carnitine shuttle activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decreases and AMP concentration increases leading to the activation ofAMP-activated protein kinase (AMPK). AMPKphosphorylatesacetyl-CoA carboxylase, which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibit carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply ofATP.[13]
Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that functions as atranscription factor. It acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation, including the fatty acid transporters carnitine acyltransferases 1 and 2, the fatty acyl–CoA dehydrogenases for short, medium, long, and very long acyl chains, and related enzymes.[13]
PPARα functions as a transcription factor in two cases; as mentioned before when there is an increased demand for energy from fat catabolism, such as during a fast between meals or long-term starvation. Besides that, the transition from fetal to neonatal metabolism in the heart. In the fetus, fuel sources in the heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel that require the PPARα to be activated so it is able in turn to activate the genes essential forfatty acid metabolism in this stage.[13]
More than 20 human genetic defects infatty acid transport oroxidation have been identified. In case offatty acid oxidation defects, acyl-carnitines accumulate in mitochondria and are transferred into the cytosol, and then into the blood. Plasma levels of acylcarnitine in newborn infants can be detected in a small blood sample bytandem mass spectrometry.[13]
Whenβ oxidation is defective because of eithermutation or deficiency in carnitine, the ω (omega) oxidation of fatty acids becomes more important in mammals. The ω oxidation of fatty acids is another pathway for F-A degradation in some species of vertebrates and mammals that occurs in the endoplasmic reticulum of the liver and kidney, it is the oxidation of the ω carbon—the carbon farthest from the carboxyl group (in contrast to oxidation which occurs at the carboxyl end offatty acid, in the mitochondria).[1][13]
Carnitine deficiency is rare in healthy people without metabolic disorders, indicating that most people have normal, adequate levels of carnitine normally produced through fatty acid metabolism.[1] One study found thatvegans showed no signs of carnitine deficiency.[14] Infants, especiallypremature infants, have low stores of carnitine, necessitating use ofcarnitine-fortifiedinfant formulas as a replacement forbreast milk, if necessary.[1]
Two types of carnitine deficiency states exist. Primary carnitine deficiency is a genetic disorder of the cellular carnitine-transporter system that typically appears by the age of five with symptoms of cardiomyopathy, skeletal-muscle weakness, and hypoglycemia.[1][3] Secondary carnitine deficiencies may happen as the result of certain disorders, such as chronickidney failure, or under conditions that reduce carnitine absorption or increase its excretion, such as the use ofantibiotics,malnutrition, and poor absorption followingdigestion.[1][3]
The plasma half-life of L-carnitine taken as a supplementation is approximately 17.4 hours.[15][8]
Despite widespread interest among athletes to use carnitine for improvement of exercise performance, inhibitmuscle cramps, or enhance recovery fromphysical training, the quality of research for these possible benefits has been low, prohibiting any conclusion of effect.[1][3] Despite some studies suggest that carnitine may improve high-intensity physical performance,[16] and facilitate recovery after such performance,[17] the results of these studies are inconclusive, since various studies used various regimens of carnitine supplementation and intensity of exercise.[18][19] At supplement amounts of 2–6 grams (0.071–0.212 oz) per day over a month, there was no consistent evidence that carnitine affected exercise or physical performance on moderate-intensity exercises, whereas on high-intensity exercises results were mixed.[3] Carnitine supplements does not seem to improve oxygen consumption or metabolic functions when exercising, nor do they increase the amount of carnitine in muscle.[1][3] The underlying mechanisms on how carnitine can improve physical performance, if at all, are not clearly understood.[20] There is no evidence that L-carnitine influencesfat metabolism or aids in weight loss.[3][21][22]
The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility.[1]
Carnitine has been studied in various cardiometabolic conditions, indicating it is under preliminary research for its potential as an adjunct inheart disease anddiabetes, among numerous other disorders.[1] Carnitine has no effect on preventingall-cause mortality associated with cardiovascular diseases,[23] and has no significant effect onblood lipids.[1][24]
Although there is some evidence frommeta-analyses that L-carnitine supplementation improved cardiac function in people withheart failure, there is insufficient research to determine its overall efficacy in lowering the risk or treatingcardiovascular diseases.[1][23]
There is only preliminaryclinical research to indicate the use of L-carnitine supplementation for improving symptoms oftype 2 diabetes, such as improvingglucose tolerance or loweringfasting levels of bloodglucose.[1][25]
The kidneys contribute to overallhomeostasis in the body, including carnitine levels. In the case ofrenal impairment, urinary elimination of carnitine increasing, endogenous synthesis decreasing, and poor nutrition as a result of disease-induced anorexia can result in carnitine deficiency.[1] Carnitine has no effect on most parameters in end-stage kidney disease, although it may lowerC-reactive protein, abiomarker for systemicinflammation.[26] Carnitine blood levels and muscle stores can become low, which may contribute toanemia, muscle weakness, fatigue, altered levels of blood fats, and heart disorders.[1] Some studies have shown that supplementation of high doses ofl-carnitine (often injected) may aid inanemia management.[1]
The form present in the body isl-carnitine, which is also the form present in food. Food sources rich inl-carnitine are animal products, particularly beef and pork.[1] Red meats tend to have higher levels ofl-carnitine.[1][24] Adults eating diverse diets that contain animal products attain about 23–135 mg of carnitine per day.[1][27] Vegans get noticeably less (about 10–12 mg) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine, then enters the blood.[1] Even carnitine-poor diets have little effect on total carnitine content, as the kidneys conserve carnitine.[24]
| Food | Milligrams (mg) |
|---|---|
| Beef steak, cooked, 4 ounces (110 g) | 56–162 |
| Ground beef, cooked, 4 ounces (110 g) | 87–99 |
| Milk, whole, 1 cup (237 g) | 8 |
| Codfish, cooked, 4 ounces (110 g) | 4–7 |
| Chicken breast, cooked, 4 ounces (110 g) | 3–5 |
| Ice cream,1⁄2 cup (125 mL) | 3 |
| Cheese, cheddar, 2 ounces (57 g) | 2 |
| Whole-wheat bread, 2 slices | 0.2 |
| Asparagus, cooked,1⁄2 cup (62 g) | 0.1 |
In general,omnivorous humans each day consume between 2 and 12 μmol/kg of body weight, accounting for 75% of carnitine in the body. Humans endogenously produce 1.2 μmol/kg of body weight of carnitine on a daily basis, accounting for 25% of the carnitine in the body.[1][3] Strict vegetarians obtain little carnitine from dietary sources (0.1 μmol/kg of body weight daily), as it is mainly found in animal-derived foods.[1][14]
L-Carnitine,acetyl-l-carnitine, and propionyl-l-carnitine are available indietary supplement pills or powders, with a daily amount of 0.5 to 1 g considered to be safe.[1][3] It is also a drug approved by theFood and Drug Administration to treat primary and certain secondary carnitine-deficiency syndromes secondary toinherited diseases.[1][3]
Carnitine interacts withpivalate-conjugated antibiotics such aspivampicillin. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion.[1] Treatment with theanticonvulsantsvalproic acid,phenobarbital,phenytoin, orcarbamazepine significantly reduces blood levels of carnitine.[4]
When taken in the amount of roughly 3 grams (0.11 oz) per day, carnitine may causenausea, vomiting, abdominal cramps,diarrhea, andbody odor smelling like fish.[1][4] Other possible adverse effects includeskin rash, muscle weakness, orseizures in people withepilepsy.[4]
Levocarnitine was approved by the U.S.Food and Drug Administration as anew molecular entity under the brand name Carnitor on December 27, 1985.[4][5]
