L-Carnitine

Mechanisms of Action

Levocarnitine facilitates long-chain fatty acid transport from the cytosol to the mitochondria, providing substrates for oxidation and subsequent cellular energy production. Levocarnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters. Levocarnitine clears the acyl CoA esters by formation of acylcarnitine which is rapidly excreted.

Carnitine acetyltransferases (CATs) catalyze the interconversion of fatty acid esters of coenzyme A and carnitine, which are located in the cytosol and mitochondrial membranes. Translocases, which exist in mitochondrial membranes, rapidly transport both free carnitine and its esters in and out of cells. Fatty acid esters of CoA, formed in the cytosol, inhibit enzymes of the Krebs cycle, and are involved in oxidative phosphorylation. Hence, the oxidation of fatty acids requires the formation of acylcarnitines and their translocation into mitochondria where the CoA esters are reformed and metabolized. If oxygen tension is limited, carnitine serves to maintain a ratio of free to esterified CoA within mitochondria that is optimal for oxidative phosphorylation and for the consumption of acetyl CoA.

General information

Levocarnitine (L-3-hydroxy-4-N-trimethylaminobutyrate) is synthesized in the liver from the amino acids methionine and lysine. This naturally occurring substance is found in all mammalian tissues, especially striated muscle, and is required in energy metabolism, such as the oxidation of fatty acids, facilitating the aerobic metabolism of carbohydrates, and enhancing the excretion of certain organic acids. While only the L isomer is present in the biologic system, commercial synthesis of carnitine produces a D,L racemic mixture, from which the L-isomer is obtained. The D-isomer has pharmacologic effects but does not participate in lipid metabolism. Commercially, carnitine is available as both a prescription and non-prescription product. The prescription version is levocarnitine, while most dietary supplements contain D,L-carnitine which is commonly sold in health food stores.

Levocarnitine has been used in the treatment of primary and secondary carnitine deficiency in adults and neonates, Alzheimer's disease, dilated cardiomyopathy in adults and children, valproic acid-induced hepatotoxicity in children, and hyperlipoproteinemia. It has been designated an orphan drug for a variety of conditions. Its use in alcohol induced fatty liver, Down's syndrome, and chronic fatigue syndrome has shown varying results. Some athletes use carnitine supplements to increase exercise performance, however, the concept of carnitine loading does not appear to be very effective.1 Further, D,L-carnitine competitively inhibits levocarnitine. This inhibition may lead to a deficiency. Prescription forms of levocarnitine were approved by the FDA in 1985 (tablets), 1986 (oral solution), and 1992 (injection).

Adverse Reactions

Gastrointestinal (GI) adverse effects are possible with oral and intravenous (IV) levocarnitine therapy. These GI symptoms include abdominal pain, dyspepsia, diarrhea, gastritis, nausea, and vomiting. These adverse effects with oral therapy may be reduced by slowing the rate of consumption and administering as divided doses throughout the day. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, GI adverse reactions were reported at the following incidence compared to placebo: abdominal pain (5—21% vs 17%), anorexia (3—6% vs 3%), constipation (3% vs 6%), diarrhea (9—35% vs 19%), dyspepsia (5—9% vs 10%), gastrointestinal disorder (2—6% vs 2%), melena (2—6% vs 3%), nausea (5—12% vs 10%), vomiting (9—21% vs 16%), weight gain (2—3% vs 2%), and weight loss (3—8% vs 3%).

Drug-induced body odor (described as "fishy" odor), headache, paresthesias and weakness have been associated with intravenous as well as oral administration of levocarnitine. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, nervous system adverse reactions were reported at the following incidence compared to placebo: headache (3—37% vs 16%), anxiety (1—2% vs 5%), asthenia (8—12% vs 8%), depression (5—6% vs 3%), dizziness (10—18% vs 11%), drug dependence (2—6% vs 2%), hypertonia (1—3% vs 5%), insomnia (3—6% vs 6%), paresthesias (3—12% vs 3%), and vertigo (2—6% vs 0%).

Levocarnitine therapy has been associated with seizures in patients with and without a history of seizures and an increase in seizure activity (frequency and/or severity). It should be administered with caution to patients with a history of seizures.

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, cardiovascular adverse reactions were reported at the following incidence compared to placebo: arrhythmia (2—3% vs 5%), atrial fibrillation (2—6% vs 0%), cardiovascular disorder (3—6% vs 6%), abnormal electrocardiogram (3—6% vs 0%), bleeding (2—9% vs 6%), chest pain (unspecified) (6—15% vs 14%), hypertension (18—21% vs 14%), hypotension (3—19% vs 19%), palpitations (3—8% vs 0%), peripheral edema (3—6% vs 3%), sinus tachycardia (5—9% vs 5%), and vascular disorder (2—6% vs 2%).2

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, respiratory and infectious adverse reactions were reported at the following incidence compared to placebo: infection (10—24% vs 17%), fever (5—12% vs 5%), bronchitis (3—5% vs 0%), cough (9—18% vs 16%), dyspnea (3—11% vs 19%), pharyngitis (15—27% vs 33%), rhinitis (6—11% vs 10%), and sinusitis (2—3% vs 5%).

During clinical trials of IV levocarnitine in patients on chronic hemodialysis, general adverse reactions were reported at the following incidence compared to placebo: anemia (3—12% vs 3%), injection site reaction (27—38% vs 59%), rash (unspecified) (3—5% vs 3%), pruritus (3—8% vs 13%), dysgeusia (2—9% vs 0%), amblyopia (3—6% vs 2%), eye disorder (3—6% vs 3%), back pain (6—9% vs 10%), parathyroid disorder (2—6% vs 2%), hypervolemia (3—12% vs 17%), hyperkalemia (6% vs 6%), and hypercalcemia (6—15% vs 3%).