Objectives: 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.
Methods: 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.
Key findings: 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).
Conclusions: 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.