A8: Antidotes in Depth

INTRODUCTION

l-Carnitine (levocarnitine) is an amino acid vital to mitochondrial utilization of fatty acids. It is approved by the US Food and Drug ­Administration (FDA) for treatment of l-carnitine deficiency that either results from inborn errors of metabolism or is associated with hemodialysis. l-Carnitine is also used off label to treat carnitine deficiency secondary to valproic acid toxicity or that associated with zidovudine (AZT)-induced mitochondrial myopathy^10,11,19 and pediatric cardiomyopathy.¹⁷

Based on the proposed mechanism of action of valproic acid–induced hyperammonemia and valproic acid–induced hepatic toxicity, l-carnitine should theoretically help with both of these conditions, but the data to support this are limited. Based on the available evidence, l-carnitine should be considered for patients with valproic acid–induced hyperammonemia and valproic acid–induced hepatic toxicity. Symptomatic patients should receive l-carnitine intravenously; because of limited bioavailability, oral administration should be reserved for patients who are not acutely ill.

HISTORY

l-Carnitine is found in mammals, in many bacteria, and in very small amounts in most plants except for avocado and soy products.³⁶ Carnitine was first discovered in 1905 in extracts of muscle, and its name is derived from carnis, the Latin word for flesh.²⁰ Subsequently, its chemical formula and structure were identified, and in 1997, its enantiomeric properties were confirmed.³⁶ Carnitine was formerly known as vitamin BT.

PHARMACOLOGY

Chemistry

Carnitine is a water-soluble amino acid that can exist as either the d- or l-form; however, the endogenous l isomer is the active form and should be used therapeutically. l-Carnitine (C₇H₁₅NO₃) has a molecular weight of 161 Da. At physiologic pH, l-carnitine contains both a positively charged quaternary nitrogen ion and a negatively charged carboxylic acid group.¹⁵

Mechanism of Action

Fatty acids provide 9 kcal/g and are important sources of human energy for the body, particularly for the liver, heart, and skeletal muscle. The utilization of fatty acids as an energy source requires l-carnitine–mediated passage through both the outer and inner mitochondrial membranes to reach the mitochondrial matrix, where β-oxidation occurs (Figs. 48–2 and 13–9). Enzymes in the outer and inner mitochondrial membranes (carnitine palmitoyltransferase and carnitine acylcarnitine translocase) catalyze the synthesis, translocation, and regeneration of l-carnitine.³² Binding of l-carnitine to fatty acids occurs through esterification at the hydroxyl group on the chiral carbon.¹⁵ The l-carnitine regenerated in the mitochondrial matrix can also translocate in the opposite direction, from the matrix and through the inner membrane back to the intermembrane space. Acyl-coenzyme A (CoA) is transported by carnitine from the cytosol to the mitochondria and undergoes β-oxidation in the mitochondrial matrix, generating acetyl-CoA, which then enters the citric ...