Pharmacokinetics of L-Carnitine

Abstract

L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.

L-Carnitine Ameliorates Glycerol-Induced Myoglobinuric Acute Renal Failure in Rats

“…administration is preferable because after oral doses of 1-6 g, the absolute bioavailability of L-carnitine is only 5-18%, mainly due to its poor absorption. [31] Unabsorbed oral Lcarnitine undergoes bacterial degradation in the gastrointestinal tract to form trimethylamine. In healthy subjects, trimethylamine, a volatile amine, is rapidly converted to trimethylamine-N-oxide and is excreted efficiently by the kidneys.…”

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

“…Carnitine, an important quaternary amine (3-hydroxy-4-N,N,N-trimethylaminobutyrate), is an essential nutrient with a major role in cellular energy production and has been considered a promising cytoprotective agent (Sayed-Ahmed, 2010). It is acquired through exogenous dietary sources, mainly from meat and milk, and its endogenous production occurs in liver by the methylation of lysine and methionine requiring the presence of iron and three vitamins: ascorbic acid, niacin, and vitamin B6 (Cerretelli & Marconi, 1990;Evans & Fornas, 2003;Ng et al, 2004). Besides, L-carnitine is essential for energy generation provided by the transportation of long-chain fatty acids into the mitochondria for beta-oxidation (Bieber, 1988).…”

Aplicações clínicas da suplementação de L-carnitina

“…O aumento do fluxo de substratos através do Ciclo de Krebs poderia resultar em produção e utilização mais efetivas do oxigênio, além da melhora na capacidade de realizar tarefas físicas. A carnitina também tem sido freqüentemente utilizada como coadjuvante no tratamento de dislipidemias, uma vez que atua como um importante co-fator na oxidação de ácidos graxos de cadeia longa, aumentando a utilização de triglicerídeos para o fornecimento de energia 1,2 .…”