4-甲基苯甲酰甘氨酸在大鼠离体灌注肾中的处置及马尿酸盐对肾线粒体代谢的影响。

Disposition of 4-methylbenzoylglycine in rat isolated perfused kidney and effects of hippurates on renal mitochondrial metabolism.

作者信息

Masereeuw R, Moons M M, Russel F G

机构信息

Department of Pharmacology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands.

出版信息

J Pharm Pharmacol. 1998 Dec;50(12):1397-404. doi: 10.1111/j.2042-7158.1998.tb03366.x.

DOI:10.1111/j.2042-7158.1998.tb03366.x

PMID:10052856

Abstract

Hippurates tend to accumulate within proximal tubule cells during renal secretion. High intracellular concentrations can alter proximal tubular function or lead to tubular toxicity. In this study we examined the renal disposition of the hippurate 4-methylbenzoylglycine, a compound known for its high renal intrinsic clearance in-vivo. The effect of intracellular accumulation on mitochondrial respiration was also measured in-vitro and compared with that of the 2-methyl and 4-amino analogues. Experiments were performed with either 2.5% pluronic or a combination of 2.2% pluronic and 2% bovine serum albumin (BSA) as oncotic agents. Within the concentration range studied (1-200 microg mL(-1)) tubular secretion seemed to be a function of the amount of unbound drug in the perfusate. Renal excretion data were best fitted by a model in which a Michaelis-Menten term was used to describe active secretion. Parameters obtained after the analysis of renal excretion data were the maximum transport velocity (TM = 55+/-2 microg min(-1)) and the Michaelis-Menten constant for tubular transport (KT = 4.2+/-0.8 microg mL(-1)). The compound accumulated extensively in kidney tissue, ratios up to 600 times the perfusate concentration were reached. Accumulation could be explained by active tubular uptake and data were analysed best by a model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity (RM =300+/-210 microg g(-1)) and affinity constant for renal accumulation (KA = 5.0+/-4.4 microg mL(-1)). The high intracellular concentrations of 4-methylbenzoylglycine had no effect on kidney function and mitochondrial oxygen consumption. The 2-methyl analogue reduced mitochondrial respiration slightly, but 4-aminobenzoylglycine (p-aminohippurate) caused a significant reduction. In conclusion, this study shows that renal accumulation of a hippurate is determined by the efficiency of its tubular secretion. Whether the high intracellular concentrations affect tubular cell functioning depends on the analogue involved.

摘要

马尿酸盐在肾脏分泌过程中往往会在近端肾小管细胞内蓄积。细胞内高浓度会改变近端肾小管功能或导致肾小管毒性。在本研究中，我们检测了马尿酸盐4-甲基苯甲酰甘氨酸在肾脏的处置情况，该化合物在体内具有较高的肾脏内在清除率。还在体外测量了细胞内蓄积对线粒体呼吸的影响，并与2-甲基和4-氨基类似物进行了比较。实验使用2.5%的普朗尼克或2.2%的普朗尼克与2%的牛血清白蛋白（BSA）组合作为渗透压剂。在所研究的浓度范围内（1 - 200 μg mL⁻¹），肾小管分泌似乎是灌注液中游离药物量的函数。肾脏排泄数据最适合用一个模型来拟合，其中米氏项用于描述主动分泌。分析肾脏排泄数据后得到的参数为最大转运速度（TM = 55 ± 2 μg min⁻¹）和肾小管转运的米氏常数（KT = 4.2 ± 0.8 μg mL⁻¹）。该化合物在肾脏组织中大量蓄积，达到的比例高达灌注液浓度的600倍。蓄积可通过肾小管主动摄取来解释，数据用类似于描述肾脏排泄的模型进行分析效果最佳。计算得到的参数为理论最大容量（RM = 300 ± 210 μg g⁻¹）和肾脏蓄积的亲和常数（KA = 5.0 ± 4.4 μg mL⁻¹）。4-甲基苯甲酰甘氨酸的高细胞内浓度对肾功能和线粒体氧消耗没有影响。2-甲基类似物轻微降低了线粒体呼吸，但4-氨基苯甲酰甘氨酸（对氨基马尿酸）导致显著降低。总之，本研究表明马尿酸盐的肾脏蓄积取决于其肾小管分泌效率。细胞内高浓度是否影响肾小管细胞功能取决于所涉及的类似物。