title: Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes.
abstract: 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 vitrohepatic 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 6beta-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 6beta-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. hanada@my-pharm.ac.jp
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hanada
authors.forename: Rie
authors.initials: R
authors.lastname: Ogawa
authors.forename: Kishin
authors.initials: K
authors.lastname: Son
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akashi
authors.initials: A
authors.lastname: Kikkawa
authors.forename: Shiho
authors.initials: S
authors.lastname: Ichihara
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogata
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007200:Indican / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D009529:Nicardipine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007210:Indoleacetic Acids; C030737:indoleacetic acid; D003577:Cytochrome P-450 Enzyme System; D009529:Nicardipine; D014453:Glucuronosyltransferase; D007200:Indican