Effect of Experimental Renal Failure on the Pharmacokinetics of Losartan in Rats
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概要
- 論文の詳細を見る
The purpose of this investigation was to determine whether the pharmacokinetics of the angiotensin II receptor antagonist losartan is altered in renal failure. Male Wistar rats were pretreated with uranyl nitrate or subjected to bilateral ureteral ligation to produce acute renal failure (ARF). Saline-injected and sham-operated rats, respectively, served as controls. Uranyl nitrate-treated rats showed significantly higher serum concentrations of losartan after oral administration and the area under the serum concentration-time curve (AUC_<0-24>) of losartan increased about 3-fold compared to control rats. The systemic clearance of losartan significantly decreased from 410±254 ml/h/kg in control to 177±112 ml/h/kg in uranyl nitrate-treated rats. In order to investigate the mechanisms of reduced clearance of losartan associated with ARF, a hepatic microsome fraction was prepared from normal and ARF rats. No significant difference was found in the metabolism of losartan by hepatic microsomes prepared from ARF and control rats. In addition, the metabolic activity of microsomes was examined in the presence of uremic rat serum. The unbound clearance of losartan and the unbound clearance associated with the formation of EXP3174 in the presence of uremic serum were significantly lower than those in the presence of control serum. Furthermore, the metabolism of losartan was inhibited by indoxyl sulfate, a uremic toxin, in an uncompetitive manner. These results suggest that ARF is associated with reduced clearance of losartan due to the inhibition of hepatic metabolism by accumulated uremic toxin(s).
- 社団法人日本薬学会の論文
- 2002-08-01
著者
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YASUHARA Masato
Department of Pharmacy, Post Graduate School, Tokyo Medical and Dental University
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Inotsume N
Department Of Hospital Pharmacy School Of Medicine Tokyo Medical And Dental University
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Inotsume Nobuo
Department Of Pharmaceutical Services Kumamoto University Hospital
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Yasuhara Masato
Department Of Hospital Pharmacy School Of Medicine Tokyo Medical And Dental University
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YOSHITANI Takashi
Department of Hospital Pharmacy, School of Medicine, Tokyo Medical and Dental University
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YAGI Hitoshi
Department of Hospital Pharmacy, School of Medicine, Tokyo Medical and Dental University
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Yoshitani T
Department Of Hospital Pharmacy School Of Medicine Tokyo Medical And Dental University
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Yoshitani Takashi
Department Of Cardiovascular Medicine Kushiro-shi Ishikai Hospital
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Yagi Hitoshi
Department Of Hospital Pharmacy School Of Medicine Tokyo Medical And Dental University
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Inotsume Nobuo
Department Of Hospital Pharmacy School Of Medicine Tokyo Medical And Dental University
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