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首页> 外文期刊>Life sciences >Kinetics of the protein-bound, lipophilic, uremic toxin p-cresol in healthy rats.
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Kinetics of the protein-bound, lipophilic, uremic toxin p-cresol in healthy rats.

机译：在健康大鼠中，蛋白质结合的亲脂性尿毒症毒素对甲酚的动力学。

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P-Cresol, a partially lipophilic and protein-bound compound is related to several biochemical alterations in uremia. Because p-cresol kinetics have never been studied, we investigated its kinetic behavior in rats. Results were compared with those obtained with creatinine, a water soluble, non-protein-bound uremic retention solute, which is currently used as a marker of uremic retention. Healthy rats were divided into 3 groups with comparable body weight: (1) a control group (n=6); (2) a group (n=7) which received an intravenous bolus of 3 mg p-cresol; and (3) a group (n=5) which received an intravenous bolus of 18 mg creatinine. Blood samples were collected at 0, 5, 30, 60, 120, 180 and 240 minutes after administration for the determination of p-cresol and creatinine. Urine was collected at 1-hour intervals. p-Cresol concentrations were assessed by HPLC. Pharmacokinetic parameters of p-cresol and creatinine were calculated from the serum concentration-time curves using non-compartmental analysis. Each compound showed a concentration at time point 5 min (p-cresol: 6.7 +/- 1.4 mg/L and creatinine: 141 +/- 12 mg/L) which was comparable with values observed in uremic patients; these concentrations decreased gradually towards min 240 (p-cresol: 0.6 +/- 0.3 mg/L and creatinine: 4 +/- 2 mg/L, p<0.05 vs. 5 min in both cases). No p-cresol was found in the serum of control rats and these rats showed no changes in serum concentration of creatinine. Urinary excretions were strikingly different (p-cresol: 23 +/- 10% and creatinine: 95 +/- 25% of the administered dose, p<0.05). The half-life of p-cresol was twice as long as that of creatinine (1.5 +/- 0.8 vs. 0.8 +/- 0.1 h, p<0.05). Total clearance (CLt) was much higher for p-cresol than for creatinine (23.2 +/- 4.5 vs. 8.1 +/- 0.4 mL/min/kg, p<0.01); renal clearance (CLr), however, was substantially lower for p-cresol (4.8 +/- 2.0 vs. 8.2 +/- 1.9 mL/min/kg, p<0.05). Whereas CLt and CLr were similar for creatinine, CLt of p-cresol largely exceeded its CLr (p<0.05). The volume of distribution (Vd) was also much larger for p-cresol than for creatinine (2.9 +/- 1.4 vs. 0.6 +/- 0.1 L/kg, p<0.01). After injection of p-cresol, an additional chromatographic peak appeared in serum and in urine samples. Although at min 240 serum concentration of p-cresol had decreased to 10% of the peak value, only 23% of the administered amount was excreted in the urine and the CLr was +/- 50% lower compared to that of creatinine. Non-renal clearance and Vd of p-cresol were, however, substantially larger. These data may be of value to explain the different behavior of p-cresol in renal failure and dialysis, compared to creatinine.
机译：P-Cresol是一种部分亲脂性的蛋白结合化合物，与尿毒症的几种生化改变有关。因为从未研究过对甲酚动力学，所以我们研究了它在大鼠中的动力学行为。将结果与使用肌酸酐（一种水溶性的，非蛋白结合的尿毒症保留溶质）获得的结果进行比较，肌酐目前被用作尿毒症保留的标志物。将健康大鼠分为体重可比的3组：（1）对照组（n = 6）; （2）一组接受3 mg对甲酚静脉推注的组（n = 7）; （3）一组（n = 5）接受18 mg肌酐静脉推注。给药后0、5、30、60、120、180和240分钟采集血样，测定对甲酚和肌酐。每隔1小时收集一次尿液。通过HPLC评估对甲酚浓度。使用非房室分析从血清浓度-时间曲线计算对甲酚和肌酐的药代动力学参数。每种化合物在5分钟时的浓度（对甲酚：6.7 +/- 1.4 mg / L，肌酐：141 +/- 12 mg / L）与尿毒症患者的观察值相当;这些浓度逐渐降低至第240分钟（对甲酚：0.6 +/- 0.3 mg / L和肌酐：4 +/- 2 mg / L，p <0.05与两种情况下的5分钟）。在对照大鼠的血清中没有发现对甲酚，并且这些大鼠的肌酸酐的血清浓度没有变化。尿液排泄显着不同（对甲酚：23 +/- 10％，肌酐：95 +/- 25％，p <0.05）。对甲酚的半衰期是肌酐的半衰期的两倍（1.5 +/- 0.8对0.8 +/- 0.1 h，p <0.05）。对甲酚的总清除率（CLt）比肌酐高得多（23.2 +/- 4.5与8.1 +/- 0.4 mL / min / kg，p <0.01）;然而，对甲酚的肾清除率（CLr）明显较低（4.8 +/- 2.0对8.2 +/- 1.9 mL / min / kg，p <0.05）。肌酐的CLt和CLr相似，对甲酚的CLt大大超过了其CLr（p <0.05）。对甲酚的分布体积（Vd）也比肌酐大得多（2.9 +/- 1.4对0.6 +/- 0.1 L / kg，p <0.01）。注射对甲酚后，血清和尿液样品中出现另一个色谱峰。尽管在第240分钟，对甲酚的血清浓度已降至峰值的10％，但与尿肌酐相比，仅23％的给药量从尿中排泄，CLr降低了+/- 50％。但是，对甲酚的非肾脏清除率和Vd明显更大。这些数据可能有助于解释与肌酐相比，对甲酚在肾衰竭和透析中的不同行为。

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