Levocarnitine (L-3-hydroxy-4-N-trimethylaminobutyrate) is synthesized from the amino acids methionine and lysine in a process that takes place in the liver. L-carnitine occurs naturally in mammalian tissue, specifically in striated muscle, and forms an essential component of energy metabolism. This includes the oxidation of fatty acids, the metabolism of carbohydrates, and the excretion of organic acids. While only the L isomer is present in body systems, commercial synthesis of carnitine produces a D,L racemic mixture, from which the L-isomer is obtained. The D-isomer does not participate in lipid metabolism. Commercially, carnitine is available in both prescription and non-prescription forms. The prescription version is levocarnitine, while most dietary supplements contain D, L-carnitine which is sold in over the counter in stores.
Levocarnitine supports the transport of long-chain fatty acids from the cytosol to the mitochondria, which in turn supports oxidation and cellular energy production. Levocarnitine can promote the excretion of excess fatty acids in patients with poor fatty acid metabolism or specific conditions that bioaccumulate acyl CoA esters. Levocarnitine clears the acyl CoA esters by forming acylcarnitine which is then excreted.
Carnitine acetyltransferases (CATs) catalyze the conversion of fatty acid esters of coenzyme A and carnitine, which are located in the cytosol and mitochondrial membranes. Translocases in mitochondrial membranes transport both free carnitine and its esters in and out of cells. Fatty acid esters of CoA inhibit the enzymes of the Krebs cycle, and contribute to oxidative phosphorylation. This means that fatty acid oxidation requires the formation of acylcarnitines and their translocation into mitochondria.
L-carnitine can be administered orally or intravenously. Levocarnitine is not bound to plasma proteins, so if plasma concentrations exceed the renal reabsorption maximum (roughly 60—100 µmol/L), excess carnitine is eliminated through the urine. Carnitine supplementation appears to have minimal effect on muscle carnitine content in humans. After administration of large doses of carnitine, most of the dose appears in the urine. Levocarnitine is metabolized in the liver, with the major metabolite, trimethylamine N-oxide, excreted rapidly. Urinary excretion of carnitine is between 4 and 8 percent of the total administered dose. Fecal excretion represents only a small percentage.
Renal Impairment: Administration of levocarnitine to patients with end-stage renal disease (ESRD) on hemodialysis results in increased plasma concentrations. For patients with renal insufficiency, the safety and efficacy of oral levocarnitine has not been evaluated. High, regular doses oral L-carnitine in patients with severe renal impairment or those on dialysis may lead to the accumulation of potentially toxic metabolites, including trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), metabolites that are normally excreted in the urine. Intravenous administration may be less likely to result in this accumulation.
Levocarnitine is used to treat carnitine deficiency in adults and neonates, also Alzheimer's disease, dilated cardiomyopathy in adults and children, valproic acid-induced hepatotoxicity in children, and hyperlipoproteinemia. L-carnitine has also been designated an orphan drug for several conditions, and has shown varying results as a treatment for alcohol induced fatty liver, Down's syndrome, and chronic fatigue syndrome. D,L-carnitine competitively inhibits levocarnitine, which may lead to a deficiency. Prescription forms of levocarnitine have been approved by the FDA as of 1985 (tablets), 1986 (oral solution), and 1992 (injection).
Levocarnitine may cause gastrointestinal symptoms and should be administered with caution to patients with existing GI issues.
Levocarnitine is classified as pregnancy category B. Reproductive studies on rats and rabbits at doses up to 3.8 times the human dose have reported no evidence of impaired fertility or harm to the fetus; at the same time, no adequate studies exist for pregnant women.
Levocarnitine therapy has been associated with an increased seizure activity and should be administered cautiously to those with seizure disorders.
Levocarnitine should be administered with caution to patients with a history of cardiac disease or cardiac dysfunction. Various cardiovascular adverse effects have been reported with IV administration of levocarnitine in dialysis patients, including hypertension, peripheral edema, and ventricular arrhythmias.
Levocarnitine administration may lead to peripheral neuropathy.
Oral levocarnitine safety and efficacy have not been evaluated for patients with renal impairment. Do not use oral formulations of levocarnitine to treat patients with severe renal impairment or renal failure, including patients on dialysis. The metabolites formed after oral administration will accumulate in patients with renal failure since they can not be efficiently removed by the kidneys. The accumulation of toxic metabolites increases the amount of nitrogenous waste to be removed in the dialysis procedure. Increased levels of TMA in dialysis patients have also been associated with neurophysiologic effects. The inefficient removal of these metabolites may give rise to a "fishy" body odor. Only the intravenous form of levocarnitine is indicated for use in ESRD patients on hemodialysis.
Use levocarnitine with caution in hepatic disease since no reliable studies are available.
Supplementation with levocarnitine in women who are breast-feeding has not been effectively studied, though levocarnitine is a normal component of human milk and is required for fat metabolism. Levocarnitine consumed within normal dietary ranges is excreted into the breast milk at a rate that is relatively constant. Women with carnitine deficiency or those nursing preterm infants may require prescription supplementation under close medical supervision. Levocarnitine supplements during nursing are unlikely to harm the infant, but over-the-counter supplements should be avoided until more research is available. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. If treatment is needed for the mother’s health, consider the discontinuation of breast feeding.
- Levocarnitine is classified as pregnancy category B. Reproductive studies performed on rats and rabbits at doses up to 3.8 times the human dose and have shown no evidence of impaired fertility or fetal harm. No adequate studies exist for pregnant women. This drug should be used during pregnancy only if necessary to the mother’s health.
- Levocarnitine supplementation during breast feeding has not been studied, though levocarnitine is a normal component of human milk and is required for fat metabolism. Supplementation within normal dietary ranges leads to relatively constant excretion into the breast-milk. Women with carnitine deficiency and those nursing preterm infants may require prescription levocarnitine supplementation under close medical supervision. It is unlikely that supplements will harm the infant, but over-the-counter supplementation should be avoided until more data is available. In nursing mothers receiving levocarnitine, any risks to the child of must be weighed against benefits to the mother. Consider discontinuing breast feeding during supplementation.
Adverse GI effects are possible with both oral and intravenous (IV) levocarnitine, and may include abdominal pain, dyspepsia, diarrhea, gastritis, nausea, and vomiting. With oral therapy, effects may be reduced by slowing the rate of consumption and dividing doses throughout the day. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, GI adverse reactions were reported compared to placebo.
Supplement-induced body odor, headache, paresthesias and weakness have been associated with intravenous and also oral administration of levocarnitine.
Levocarnitine therapy has been associated with seizures in patients with and without a history of seizures. Patients with a history of seizures should be given this therapy with caution.
During clinical trials of IV levocarnatine in patients on chronic hemodialysis, cardiovascular adverse reactions were reported compared to placebo.
During clinical trials of IV levocarnatine in patients on chronic hemodialysis, respiratory and infectious adverse reactions were reported compared to placebo.
During clinical trials of IV levocarnitine in patients on chronic hemodialysis, general adverse reactions were reported compared to placebo, including: anemia, injection site reaction, rash (unspecified), pruritus, dysgeusia, amblyopia, eye disorder, back pain, parathyroid disorder, hypervolemia, hyperkalemia, and hypercalcemia.