Inhibitory effects of uraemic toxins 3-indoxyl sulfate and p-cresol on losartan metabolism in vitro.
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.
Tsujimoto
Masayuki
M
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. tsujimt@mb.kyoto-phu.ac.jp
Higuchi
Keishi
K
Shima
Daisuke
D
Yokota
Hitoshi
H
Furukubo
Taku
T
Izumi
Satoshi
S
Yamakawa
Tomoyuki
T
Otagiri
Masaki
M
Hirata
Sumio
S
Takara
Kohji
K
Nishiguchi
Kohshi
K
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
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