Pace S, Longo A, Toon S, Rolan P, Evans A M
Sigma Tau Industrie Farmaceutiche Riunite s.p.a., Pomezia, Rome, Italy.
Br J Clin Pharmacol. 2000 Nov;50(5):441-8. doi: 10.1046/j.1365-2125.2000.00280.x.
Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride.
This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c.
All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC.
Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
丙酰-L-肉碱（PLC）是一种内源性化合物，它与L-肉碱（LC）和乙酰-L-肉碱（ALC）一起，构成了人类以及大多数（如果不是所有的）动物物种内源性肉碱池的一个组成部分。目前正在研究PLC用于治疗外周动脉疾病，本研究旨在评估静脉注射盐酸丙酰-L-肉碱的药代动力学。
这是一项安慰剂对照、双盲、平行组、剂量递增研究，将24名健康男性分为四组，每组6人。每组中有4名受试者接受盐酸丙酰-L-肉碱，2名接受安慰剂。剂量（1g、2g、4g和8g）以恒定速率在2小时内输注，从输注开始收集24小时的血液和尿液。血浆和尿液中的PLC、ALC和LC通过高效液相色谱法定量。
所有24名受试者均成功完成研究，输注耐受性良好。静脉注射盐酸丙酰-L-肉碱后，除了PLC水平预期升高外，LC和ALC的血浆浓度和尿排泄量也高于基线值。在1g剂量时，发现PLC的平均（±标准差）半衰期为1.09±0.15小时，清除率为11.6±0.24 l h⁻¹，分布容积为18.3±2.4 l。这些参数均不随剂量变化。在接受安慰剂治疗的受试者中，内源性PLC、LC和ALC经历了广泛的肾小管重吸收，肾小管排泄清除率与肾小球滤过率的比值小于0.1表明了这一点。PLC的肾小管排泄清除率在基线条件下为0.33±0.38 l h⁻¹，在1g剂量时从1.98±0.59 l h⁻¹增加到8g剂量时的5.55±1.50 l h⁻¹（差异的95%置信区间为2.18,4.97）（P < 0.001）。因此，尿液中以原形排泄的剂量百分比从18.1±5.5%（1g）增加到50.3±13.3%（8g）（P < 0.001）。PLC给药后，LC和ALC的肾小管排泄清除率也大幅增加，并且有证据表明PLC在肾脏代谢为LC和ALC。
静脉注射盐酸丙酰-L-肉碱导致PLC、LC和ALC的肾小管排泄清除率显著增加，这是由于肾小管重吸收过程饱和所致——因此，尿液中以原形排泄的部分随剂量大幅增加。尽管PLC的肾脏清除率显著增加，但总清除率保持不变，这表明该化合物通过非排泄途径的清除有代偿性降低。
