Chapter A10: L-Carnitine

INTRODUCTION

L-Carnitine (levocarnitine) is an amino acid vital to the 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 metabolism³¹ or is associated with hemodialysis. L-Carnitine is also used to treat carnitine deficiency secondary to valproic acid or that associated with zidovudine (AZT)-induced mitochondrial myopathy.^11,12,21

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 is recommended for patients with valproic acid–induced hyperammonemia and valproic acid–induced hepatic toxicity. Because of limited bioavailability, symptomatic patients should receive L-carnitine intravenously, with oral administration 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.⁴⁴ Carnitine was first discovered in 1905 in extracts of muscle, and its name is derived from carnis, the Latin word for flesh.²² Subsequently, its chemical formula and structure were identified, and in 1997, its enantiomeric properties were confirmed.⁴⁴ Carnitine was formerly known as vitamin BT.

PHARMACOLOGY

Chemistry

Carnitine is a water-soluble amino acid that exists in either the D- or L-form; however, the endogenous L isomer is the active form and which is used therapeutically. L-Carnitine 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.¹⁶

Mechanism of Action

Fatty acids provide 9 kcal/g and are important sources of human energy, 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. 11–10 and 48–3). Enzymes in the outer and inner mitochondrial membranes (carnitine palmitoyltransferase and carnitine acylcarnitine translocase) catalyze the synthesis, translocation, and regeneration of L-carnitine.³⁹ Binding of L-carnitine to fatty acids occurs through esterification at the hydroxyl group on the chiral carbon.¹⁶ 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 tricarboxylic acid cycle for the generation of adenosine triphosphate (ATP).

L-Carnitine Homeostasis