Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes.
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.
Hanada
Kazuhiko
K
Department of Biopharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. hanada@my-pharm.ac.jp
Ogawa
Rie
R
Son
Kishin
K
Sasaki
Yuuki
Y
Kikkawa
Akashi
A
Ichihara
Shiho
S
Ogata
Hiroyasu
H
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
D015415:Biomarkers; D007210:Indoleacetic Acids; C030737:indoleacetic acid; D003577:Cytochrome P-450 Enzyme System; D009529:Nicardipine; D014453:Glucuronosyltransferase; D007200:Indican