title: Inhibitory effects of uraemic toxins 3-indoxyl sulfate and p-cresol on losartan metabolism in vitro.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
authors: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. tsujimt@mb.kyoto-phu.ac.jp
authors: Masayuki
authors: M
authors: Tsujimoto
authors: Keishi
authors: K
authors: Higuchi
authors: Daisuke
authors: D
authors: Shima
authors: Hitoshi
authors: H
authors: Yokota
authors: Taku
authors: T
authors: Furukubo
authors: Satoshi
authors: S
authors: Izumi
authors: Tomoyuki
authors: T
authors: Yamakawa
authors: Masaki
authors: M
authors: Otagiri
authors: Sumio
authors: S
authors: Hirata
authors: Kohji
authors: K
authors: Takara
authors: Kohshi
authors: K
authors: Nishiguchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003408:Cresols / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D066298:In Vitro Techniques; D007200:Indican / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D019808:Losartan / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D006435:Renal Dialysis; D013777:Tetrazoles / Q000378:metabolism*; D014511:Uremia / Q000503:physiopathology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D003408:Cresols; D007093:Imidazoles; D013777:Tetrazoles; C032538:4-cresol; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C066026:losartan carboxylic acid; D019808:Losartan; D007200:Indican