Lesaffer Gerrit, De Smet Rita, D'Heuvaert Tommy, Belpaire Frans M, Lameire Norbert, Vanholder Raymond
Department of Pharmacology, Heymans Institute, University Hospital, Gent, Belgium.
Kidney Int. 2003 Oct;64(4):1365-73. doi: 10.1046/j.1523-1755.2003.00228.x.
p-cresol, which is extensively metabolized into p-cresylglucuronide in the rat, is related to several biochemical and physiologic alterations in uremia and is not removed adequately by current hemodialysis strategies. The knowledge of its in vivo kinetic behavior could be helpful to improve the current removal strategies.
We investigated the kinetic behavior of intravenously injected p-cresol (10 mg/kg) in rats with normal and decreased renal function, and compared the results with those obtained for creatinine (60 mg/kg) under similar conditions. Renal failure was obtained by 5/6 nephrectomy. Both p-cresol and p-cresylglucuronide were analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). The relation between the p-cresylglucuronide peak height and the underlying amount of p-cresol was determined after hydrolysis of the glucuronide with beta-glucuronidase. We calculated urinary excretion of p-cresol with and without taking p-cresylglucuronide into account. In addition, total, renal, and non-renal clearance, half-life, and volume of distribution were calculated for p-cresol.
Over a 4-hour period, p-cresol serum concentration showed only a minimal decline in rats with decreased renal function (t1/2 = 11.7 +/- 0.4 hours), compared to rats with normal renal function (t1/2 = 1.4 +/- 0.7 hours). A similar observation was made for p-cresylglucuronide. In rats with normal renal function, 21.0 +/- 10.0% of the injected p-cresol was excreted in urine as p-cresol and 60.7 +/- 25.0% as p-cresylglucuronide; in rats with renal failure, the respective amounts were 6.7 +/- 7.5% and 32.0 +/- 25.3% (P < 0.05 vs. normal renal function) (total recovery 81.81 +/- 31.07% vs. 38.50 +/- 32.09%, P < 0.05). The volume of distribution of p-cresol was approximately 4 times larger than that of creatinine, but was not significantly affected by renal failure. Not only renal, but also non-renal and total clearance, were much lower in rats with decreased renal function.
The present data sheds a light on the kinetic behavior of p-cresol in uremic patients; the large volume of distribution, especially, might explain the inadequate dialytic removal of p-cresol. In addition, a substantial amount of p-cresol is removed by metabolism, and both renal and non-renal clearance are disturbed in uremia.
对甲酚在大鼠体内可广泛代谢为对甲酚葡萄糖醛酸苷，它与尿毒症的多种生化和生理改变有关，且目前的血液透析策略无法充分清除它。了解其体内动力学行为可能有助于改进当前的清除策略。
我们研究了静脉注射对甲酚（10mg/kg）在肾功能正常和降低的大鼠体内的动力学行为，并将结果与在类似条件下对肌酐（60mg/kg）的研究结果进行比较。通过5/6肾切除术诱导肾衰竭。使用反相高效液相色谱法（RP-HPLC）分析对甲酚和对甲酚葡萄糖醛酸苷。在用β-葡萄糖醛酸酶水解葡萄糖醛酸苷后，确定对甲酚葡萄糖醛酸苷峰高与对甲酚潜在量之间的关系。我们计算了考虑和不考虑对甲酚葡萄糖醛酸苷时对甲酚的尿排泄量。此外，还计算了对甲酚的总清除率、肾清除率、非肾清除率、半衰期和分布容积。
在4小时内，与肾功能正常的大鼠（t1/2 = 1.4 +/- 0.7小时）相比，肾功能降低的大鼠对甲酚血清浓度仅出现极小的下降（t1/2 = 11.7 +/- 0.4小时）。对对甲酚葡萄糖醛酸苷也有类似的观察结果。在肾功能正常的大鼠中，注射的对甲酚有21.0 +/- 10.0%以对甲酚形式经尿液排泄，60.7 +/- 25.0%以对甲酚葡萄糖醛酸苷形式排泄；在肾衰竭大鼠中，相应的量分别为6.7 +/- 7.5%和32.0 +/- 25.3%（与肾功能正常组相比，P < 0.05）（总回收率81.81 +/- 31.07%对38.50 +/- 32.09%，P < 0.05）。对甲酚的分布容积约为肌酐的4倍，但不受肾衰竭的显著影响。肾功能降低的大鼠不仅肾清除率，而且非肾清除率和总清除率都低得多。
目前的数据揭示了对甲酚在尿毒症患者体内的动力学行为；特别是较大的分布容积可能解释了对甲酚透析清除不充分的原因。此外，大量的对甲酚通过代谢被清除，并且在尿毒症中肾清除率和非肾清除率均受到干扰。
