A pharmacokinetic model for L‐carnitine in patients receiving haemodialysis

Abstract

What is already known about this subject • Carnitine is essential for fatty acid metabolism, and is obtained from the diet and endogenous synthesis. • Patients with renal failure who are on chronic haemodialysis may require carnitine supplementation. • It is known that carnitine depletion in these patients may take years to develop, and that measurements of plasma carnitine may not be predictive of loss of carnitine from muscle, the main pool of carnitine in the body. What this study adds • This paper adds a quantitative understanding of the time‐course of the relationship between haemodialysis and the plasma concentration of L‐carnitine, with particular reference to how the carnitine pools in the body re‐equilibrate after a dialysis session. • It also provides insight into the time‐course of the depletion of L‐carnitine in these patients. Aims Patients requiring chronic haemodialysis may develop a secondary carnitine deficiency through dialytic loss of L‐carnitine. A previous report has described the plasma concentrations of L‐carnitine in 12 such patients under baseline conditions and after L‐carnitine administration (20 mg kg−1). A three‐compartment pharmacokinetic model was developed to describe these data to make inferences about carnitine supplementation in these patients. Methods L‐carnitine removal was mediated solely by intermittent haemodialysis, which was incorporated into the model as an experimentally derived dialysis clearance value that was linked to an on‐off pulse function. Data were described by a model with a central compartment linked to ‘fast’‐ and ‘slow’‐equilibrating peripheral compartments. Results The model adequately described the changing plasma concentrations of endogenous L‐carnitine in individual haemodialysis patients. Based on pooled data (mean ± SD; n = 12), the volume of the central compartment was 10.09 ± 0.72 l and the transfer rate constants into and out of the slowly equilibrating pool were 0.100 ± 0.018 h−1 and 0.00014 ± 0.00016 h−1, respectively. The turnover time of L‐carnitine in the slow pool (which was assumed to represent muscle) was approximately 300 days. The model was in general agreement with separate data on the measured loss of carnitine from muscle in dialysis patients. Conclusions Haemodialysis causes rapid reductions in plasma L‐carnitine concentrations with each dialysis session. Plasma concentrations are restored between sessions by redistribution from peripheral compartments. However, during chronic haemodialysis, the ongoing dialytic loss of L‐carnitine may lead to a slow depletion of the compound, contributing to a possible secondary deficiency.

Impact on L‐carnitine Homeostasis of Short‐term Treatment with the Pivalate Prodrug Tenofovir Dipivoxil

“…Previous studies have shown that plasma L-carnitine level was decreased in patients with antiretroviral toxic neuropathy, and oral L-carnitine supplementation seems to result in plasma levels that are higher than in healthy individuals [16,17]. So, the recommended dose for patients need to be further studied due to the close relationship between the endogenous L-carnitine level and pathological state.…”

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

“…Undoubtedly, L-carnitine is effective for the treatment of inherited disorders related to functional anomalies in a specific organic cation/carnitine transporter (OCTN2), in drug-induced Lcarnitine deficiency and in cases of excessive excretion of L-carnitine because of renal tubular disorders and in patients on haemodialysis (Angelini et al, 2006;Fornasini et al, 2007;Lheureux et al, 2005). The safety profile of L-carnitine allows its frequent use in cocktails of food additives that are aimed to increase the oxidation of FA to eliminate body fat and thus produce cosmetic effects.…”

L-carnitine in Hyperammonemia and Hepatic Encephalopathy

“…Secondary L-carnitine deficiency occurs due to genetically defined disturbances in fatty acid oxidation and amino acid homeostasis. Several medical conditions, such as cirrhosis and other metabolic disorders, lead to secondary L-carnitine deficiency, as well as hemodialysis or kidney failure (Fornasini et al, 2007, Virmani & Binienda, 2004. Both disorders induce the same symptoms, like periodic encephalopathies which often come along with www.intechopen.com hypoglycemia and hypoketonia.…”