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
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 acid cycle for the generation of adenosine triphosphate (ATP).
Approximately 54% to 87% of the body stores of l-carnitine is derived primarily from meat and dairy products in the diet; the remainder is endogenously synthesized from trimethyllysine.36 This amino acid, found largely in skeletal muscle, is converted to trimethylammoniobutanoate (γ-butyrobetaine) and then carried to the liver and kidney for hydroxylation to l-carnitine.20 Synthesis of l-carnitine in the liver and kidney occurs at a rate of approximately 2 μmol/kg/d and is regulated by the amount of diet-derived trimethyllysine.20,36l-Carnitine is filtered by the kidneys, and tubular reabsorption maintains serum l-carnitine concentrations in the normal range, which is approximately 40 to 50 μmol/L.37
Pharmacokinetics of Exogenous l-Carnitine
Carnitine pharmacokinetics is very complex and must take into consideration extensive interconversion between l-carnitine and acylcarnitine as well as multicompartmental nonlinear pharmacokinetic modeling.37 The current understanding of l-carnitine pharmacokinetics is largely derived from three major studies.9,18,43l-Carnitine is not bound to plasma proteins. Its volume of distribution (Vd) of the central compartment (Vc) is 0.15 L/kg, approximating extracellular fluid volume. Its Vd is 0.7 L/kg. Both vary depending on the compartment model analyzed. The α half-life is 0.6 to 0.7 hours, with a terminal elimination half-life of 10 to 23 hours, but may be 25% to 50% shorter. The kidneys rapidly eliminate l-carnitine, and as the dose increases, renal clearance increases, reflecting saturation of renal reuptake by organic cation/carnitine transporter.37 Baseline serum concentrations for l-carnitine are 40 μmol/L but increase to a peak concentration of 1000 μmol/L after 2 g of l-carnitine are administered intravenously. Oral (PO) administration of 2 g produces peaks of only 15 to 70 μmol/L, demonstrating poor oral bioavailability. The time to peak concentrations after PO administration occurs at 2.5 to 7.0 hours, indicating slow uptake and release by intestinal mucosal cells. After a 2 g carnitine dose, PO absorption is rapidly saturated, and no further absorption occurs after administration of 6 g PO. After a radiolabeled dose, most l-carnitine is metabolized to trimethylamine N-oxide and butyrobetaine, with only approximately 4% to 8% remaining unchanged. The metabolites trimethylamine and trimethylamine N-oxide may accumulate after chronic high-dose PO therapy in patients with severely compromised kidney function.9 Fecal excretion of l-carnitine is less than 1% of the total dose. Carnitor (l-carnitine) tablets are bioequivalent to the Carnitor PO solution, with a bioavailability of approximately 15%. After 4 days of dosing at 1980 mg (6 × 330-mg tablets) twice daily or 2 g twice daily of the PO solution, the maximum serum concentration was 80 μmol/L.