Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
J Pharm Pharmacol. 2010 Jan;62(1):133-8. doi: 10.1211/jpp.62.01.0015.
The purpose of this study was to clarify the cause of decreased metabolic clearance of losartan in patients with end-stage renal failure. The influence of serum from haemodialysis patients (uraemic serum) and uraemic toxins on the metabolism of losartan to EXP-3174 was investigated in vitro.
The formation of EXP-3174 was estimated using pooled human liver microsomes. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, 3-indoxyl sulfate and p-cresol were used as uraemic toxins.
Uraemic serum potently decreased the formation of EXP-3174 in pooled human liver microsomes. In addition, 3-indoxyl sulfate and p-cresol significantly decreased the formation of EXP-3174 in a concentration-dependent manner. Furthermore, normal serum (10% v/v) with both 3-indoxyl sulfate and p-cresol (both 20 micromol/l) significantly decreased the formation of EXP-3174 by 46%, which was similar to the level of inhibition with uraemic serum (10% v/v).
These results suggest that decreased the metabolic clearance of losartan in patients with end-stage renal failure is partly due to high concentrations of 3-indoxyl sulfate and p-cresol.
本研究旨在阐明终末期肾衰竭患者洛沙坦代谢清除率降低的原因。在体外研究了血液透析患者的血清（尿毒症血清）和尿毒症毒素对洛沙坦转化为 EXP-3174 的代谢的影响。
使用人肝微粒体混合物来评估 EXP-3174 的形成。3-羧基-4-甲基-5-丙基-2-呋喃丙酸、马尿酸、吲哚-3-乙酸、3-吲哚硫酸和对甲酚用作尿毒症毒素。
尿毒症血清可显著降低人肝微粒体混合物中 EXP-3174 的形成。此外，3-吲哚硫酸和对甲酚呈浓度依赖性显著降低 EXP-3174 的形成。此外，正常血清（10%v/v）与 3-吲哚硫酸和对甲酚（均为 20 μmol/l）一起可使 EXP-3174 的形成显著降低 46%，与尿毒症血清（10%v/v）的抑制水平相似。
这些结果表明，终末期肾衰竭患者洛沙坦代谢清除率降低部分是由于 3-吲哚硫酸和对甲酚浓度升高所致。
