L-carnitine for valproic acid-induced toxicity.

Abstract

Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.