期刊
NEPHRON PHYSIOLOGY
卷 103, 期 4, 页码 179-186出版社
KARGER
DOI: 10.1159/000092919
关键词
uremic substances; metabolism; microsomes; hepatocytes; pharmacokinetics; 3-indoxylsulfate; 3-indoleacetic acid; nicardipine; testosterone to 6 beta-hydroxyltestosterone
Background: Alterations of hepatic drug metabolism in patients with renal failure are poorly understood. In this study, the effects of uremic substances that can be removed by hemodialysis on in vitro hepatic drug metabolism were studied using human liver microsomes and hepatocytes. Methods: The metabolism of various compounds that undergo oxidation and glucuronidation in the liver was studied using human liver microsomes and hepatocytes in the presence of 11 uremic substances removable by hemodialysis. Results: The formation of resorufin from ethoxyresorufin was inhibited by 3-indoxylsulfate and 3-indoleacetic acid. The formation of 6 beta-hydroxytestosterone from testosterone was inhibited only by 3-indoxylsulfate. These uremic substances reduced the maximum metabolic rate but not the affinity, suggesting that the inhibitory mechanism was noncompetitive. The inhibition of formation of resorufin and 6 beta-hydroxytestosterone by 3-indoxylsulfate was also observed in human hepatocytes. The elimination of nicardipine in liver microsomes was decreased significantly in the presence of 3-indoxylsulfate and 3-indoleacetic acid. Conclusion: The hepatic metabolism of certain drugs may be inhibited directly by uremic substances such as 3-indoxylsulfate that accumulate in the plasma in patients with chronic renal failure. Copyright (c) 2006 S. Karger AG, Basel.
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