Inhibitory effects of uraemic toxins 3‐indoxyl sulfate and p‐cresol on losartan metabolism in vitro

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 μmol/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.