LEVOCARNITINE

Indications

• Primary carnitine deficiency due to inborn errors of metabolism
• Secondary carnitine deficiency in patients undergoing haemodialysis
• Management of certain metabolic disorders associated with carnitine deficiency

Dosage

Adults: Initially, 20 mg/kg by slow intravenous injection after each dialysis session, with dosage adjusted according to plasma-carnit

Mechanism of action

Levocarnitine transports long-chain fatty acids into the mitochondria for β-oxidation, which generates energy. It also exports acyl groups from subcellular organelles to prevent toxic accumulation. Levocarnitine acts as a peripheral antagonist of thyroid hormone action in some tissues, inhibiting thyroid hormone entry into cell nuclei. It is involved in several pathways, including carnitine transporters, translocases, acetyltransferases, and palmitoyltransferases, contributing to metabolic processes.

Pharmacodynamics

Levocarnitine is crucial for the transport of fatty acids into mitochondria for energy production. A deficiency can lead to serious metabolic issues, including liver, heart, and muscle dysfunction. Biochemical deficiency is indicated by low plasma concentrations of free carnitine and elevated acylcarnitine levels. Levocarnitine enhances gastric and pancreatic secretions and can aid in managing hyperlipoproteinemias.

Pharmacokinetics

Levocarnitine is absorbed through the gastrointestinal tract, and its bioavailability can vary based on the formulation. After absorption, it is distributed throughout the body, particularly in tissues with high energy demands such as the heart and skeletal muscles. The elimination half-life is approximately 4 hours, with renal excretion of metabolites being the primary route of elimination. The pharmacokinetics may be affected in individuals with renal impairment, leading to potential accumulation.

Contra-indications

• Hypersensitivity to levocarnitine or any of its excipients
• Severe renal impairment

Adverse effects

• Abdominal pain
• Diarrhoea
• Flatulence
• Nausea
• Vomiting
• Abdominal cramps
• Increased risk of infection
• Skin odour
• Uncommon cases of seizures

Interactions

• May interact with thyroid hormones, potentially altering their effects
• Caution in patients taking anticoagulants due to potential alteration in metabolism

Precautions

• Monitor patients with diabetes mellitus for blood glucose levels
• Caution in hepatic impairment as limited data is available
• Use with caution in patients with renal impairment due to risk of accumulation
• Monitor carnitine levels to avoid potential toxicity

Pregnancy

Avoid unless absolutely necessary, as animal studies indicate potential toxicity.

Breast-feeding

Avoid-levocarnitine is present in milk in animal studies.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Levocarnitine 1.5g/5ml oral solution
• Levocarnitine 200 mg/ml solution for injection
• Levocarnitine 1g chewable tablets

Mechanism of action

Levocarnitine can be synthesised within the body from the amino acids lysine or methionine. Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. Only the L isomer of carnitine (sometimes called vitamin BT) affects lipid metabolism. Levocarnitine is handled by several proteins in different pathways including carnitine transporters, carnitine translocases, carnitine acetyltransferases and carnitine palmitoyltransferases. L-Carnitine is a peripheral antagonist of thyroid hormone action in some tissues. It inhibits thyroid hormone entry into cell nuclei. In a controlled clinical trial, L-carnitine was shown to reverse or prevent some symptoms of hyperthyroidism. ... Mortality and metabolic consequences of acute ammonium intoxication in mice are reduced by pharmacologic admin of L-carnitine. The mechanism for this effect may have 2 components. L-Carnitine admin normalizes the redox state of the brain (perhaps by incr the avail of beta-hydroxybutyrate and/or acetyl-L-carnitine to the brain), and it incr the rate of urea synth in the liver, perhaps in part by activation of the glucocorticoid receptor. At least part of the protective effect is associated with flux through the carnitine acyltransferases, as analogs of L-carnitine that are competitive inhibitors of carnitine acyltransferases enhance the toxicity of acute ammonium admin. Thus, it has been proposed that L-carnitine incr urea synth in the liver by facilitating fatty acid entry into mitochondria, leading to incr flux through the beta-oxidation pathway, an incr of intramitochondrial reducing equivalents, and enhancement of ATP production. ... Levocarnitine is necessary for normal mammalian fat utilization and energy metabolism. It facilitates entry of long-chain fatty acids into cellular mitochondria, where they are used during oxidation and energy production. It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. Carnitine's primary mechanism of action is apparently attributable to its role as a cofactor in the transformation of free long-chain fatty acids into acylcarnitines for subsequent transport into the mitochondrial matrix. Carnitine is involved in the metabolism of ketones for energy and the conversion of branched-chain amino acids - valine, leucine, and isoleucine - into energy. /Carnitine/ L-Carnitine participates in a reversible transesterification reaction, in which an acyl group is transferred from coenzyme A to the hydroxyl group of L-carnitine ... /This reaction facilitates the/ transfer of long-chain fatty acids from cytoplasm ... /and/ chain-shortened /very-long-chain/ fatty acids from peroxisomes to mitochondria /and the/ modulation of the acyl-CoA/CoA ratio in cellular compartments.

Pharmacodynamics

Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. Lack of carnitine can lead to liver, heart, and muscle problems. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. Only the L isomer of carnitine (sometimes called vitamin BT) affects lipid metabolism. The "vitamin BT" form actually contains D,L-carnitine, which competitively inhibits levocarnitine and can cause deficiency. Levocarnitine can be used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias.