Evans Allan M, Fornasini Gianfranco
Centre for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Adelaide, South Australia, Australia.
Clin Pharmacokinet. 2003;42(11):941-67. doi: 10.2165/00003088-200342110-00002.
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.
左旋肉碱是一种天然存在的化合物，可促进脂肪酸进入线粒体进行β氧化。外源性左旋肉碱在临床上用于治疗肉碱缺乏症及一系列其他病症。在人体中，内源性肉碱池由游离左旋肉碱以及一系列短链、中链和长链酯组成，通过从饮食来源吸收左旋肉碱、体内生物合成以及从肾小球滤液中进行广泛的肾小管重吸收来维持。此外，载体介导的转运可确保在严重依赖脂肪酸氧化的组织中，组织与血浆的浓度比很高。口服后，左旋肉碱的吸收部分通过载体介导的转运，部分通过被动扩散。口服1 - 6克剂量后，绝对生物利用度为5 - 18%。相比之下，饮食中左旋肉碱的生物利用度可能高达75%。因此，左旋肉碱的药理剂量或补充剂量的吸收效率低于正常饮食中相对较少的量。左旋肉碱及其短链酯不与血浆蛋白结合，尽管血细胞中含有左旋肉碱，但在全血中红细胞与血浆之间的分布速率极慢。静脉给药后，左旋肉碱的初始分布容积通常约为0.2 - 0.3升/千克，这与细胞外液容积相对应。左旋肉碱至少有三个不同的药代动力学隔室，平衡最慢的隔室包括骨骼肌和心肌。左旋肉碱主要通过尿液排泄从体内消除。在基线条件下，左旋肉碱的肾清除率（1 - 3毫升/分钟）远低于肾小球滤过率（GFR），表明存在广泛的（98 - 99%）肾小管重吸收。肾小管重吸收的阈值浓度（超过该浓度分数重吸收开始下降）约为40 - 60微摩尔/升，这与内源性血浆左旋肉碱水平相似。因此，外源性给药后左旋肉碱的肾清除率会增加，高静脉剂量后接近GFR。原发性肉碱缺乏症患者在左旋肉碱的肾脏处理和/或该化合物向肌肉组织的转运方面表现出改变。同样，许多形式的继发性肉碱缺乏症，包括一些药物引起的病症，都源于肾小管重吸收受损。接受透析的终末期肾病患者可能会因通过透析器无限制地丢失左旋肉碱而出现继发性肉碱缺乏症，并且左旋肉碱已被用于治疗一些长期血液透析患者。最近的研究已开始揭示左旋肉碱在血液透析患者中使用时的药代动力学情况。
