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透析相关的肉碱紊乱与左卡尼汀药理学

Dialysis-related carnitine disorder and levocarnitine pharmacology.

作者信息

Evans Allan

机构信息

Centre for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Adelaide, South Australia.

出版信息

Am J Kidney Dis. 2003 Apr;41(4 Suppl 4):S13-26. doi: 10.1016/s0272-6386(03)00113-6.

Abstract

Among the homeostatic processes controlling the endogenous L-carnitine pool in humans, the kidney has a vital role through extensive and adaptive tubular reabsorption. Kidney disease can lead to disturbances in L-carnitine homeostasis, and long-term hemodialysis therapy can lead to a significant reduction in plasma and tissue L-carnitine levels and an increase in the ratio of acyl-L-carnitine to free L-carnitine. These alterations may interfere with the oxidation of fatty acids and removal from tissues of unwanted short-chain acyl groups. A dialysis-related carnitine disorder (DCD) arises when these biochemical abnormalities exist in association with such clinical symptoms as muscle weakness, cardiomyopathy, intradialytic hypotension, or anemia that is resistant to erythropoietin therapy. Exogenous L-carnitine, administered intravenously, is approved for the treatment of secondary carnitine deficiency caused by long-term hemodialysis. Although intravenous administration of 20-mg/kg doses at the end of each hemodialysis session leads to supraphysiological levels of the compound in plasma, these levels do not appear to be associated with adverse effects. Because more than 99% of the body's carnitine pool is located outside of plasma, supraphysiological plasma levels appear to be required to ensure that depleted muscle stores can be replenished. Although oral L-carnitine has been used for the treatment of DCD, the bioavailability of oral L-carnitine is low (<15%) in healthy subjects and unknown in patients with end-stage renal disease. Moreover, gastrointestinal degradation of L-carnitine to trimethylamine and other compounds might limit the usefulness of long-term oral L-carnitine administration in this patient group.

摘要

在控制人体内源性左旋肉碱储备的稳态过程中,肾脏通过广泛且适应性的肾小管重吸收发挥着至关重要的作用。肾脏疾病可导致左旋肉碱稳态失衡,长期血液透析治疗可导致血浆和组织中左旋肉碱水平显著降低,以及酰基左旋肉碱与游离左旋肉碱的比值升高。这些改变可能会干扰脂肪酸的氧化以及从组织中清除不需要的短链酰基。当这些生化异常与肌肉无力、心肌病、透析中低血压或对促红细胞生成素治疗耐药的贫血等临床症状同时存在时,就会出现与透析相关的肉碱紊乱(DCD)。静脉注射外源性左旋肉碱被批准用于治疗长期血液透析引起的继发性肉碱缺乏。尽管在每次血液透析结束时静脉注射20mg/kg剂量会使血浆中该化合物的水平超过生理水平,但这些水平似乎与不良反应无关。由于人体超过99%的肉碱储备位于血浆之外,似乎需要超出生理水平的血浆浓度来确保耗尽的肌肉储备能够得到补充。尽管口服左旋肉碱已被用于治疗DCD,但在健康受试者中口服左旋肉碱的生物利用度较低(<15%),而在终末期肾病患者中则未知。此外,左旋肉碱在胃肠道降解为三甲胺和其他化合物可能会限制该患者群体长期口服左旋肉碱的有效性。

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