L-carnitine is an essential co-factor 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. 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. 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. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14-18%. 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 re-absorption at supra-physiological concentrations. 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 which are currently advocated.

Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30g or 500mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. Small studies in patients whose paracetamol concentration are above the 300mg/L nomogram line show that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22h may reduce the risk of hepatotoxicity (peak ALT>1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.