Glucuronidation and the transport of the glucuronide metabolites in LLC-PK1 cells.
Formation and transport of glucuronide metabolites were studied in LLC-PK1 cells. Glucuronidation of 17beta-estradiol, 1-naphthol, mycophenolic acid, and 4-methylumbelliferone was examined in microsomes prepared from LLC-PK1 cells, human livers, human kidneys, and human intestines. The rate of glucuronide metabolite formation observed with LLC-PK1 microsomes was comparable to rates observed with various human tissue microsomes. The fate of the glucuronide metabolite formed in the LLC-PK1 cells was studied by examining its extracellular transport using mycophenolic acid as a model substrate. After administration of mycophenolic acid, the amount of the glucuronide metabolite exiting to the extracellular compartments significantly decreased in the presence of MK-571, an inhibitor for the multidrug resistance-associated protein (MRP) transporter. However, the intracellular levels of the glucuronide metabolite did not change, suggesting that MK-571 was probably blocking metabolite efflux. In summary, these results suggest that the glucuronidating enzyme(s) expressed in the LLC-PK1 cells are capable of sufficient glucuronidation activity and that endogenous transporter(s) in LLC-PK1 cells are active and determine the distribution of the formed metabolites. Since these cells have been previously used to study drug transport, they may be a useful tool in future studies to explore the effect of drug transporters on glucuronidation.
Chang
Jae H
JH
Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94143, USA.
Benet
Leslie Z
LZ
D000818:Animals; D001692:Biological Transport; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D018374:LLC-PK1 Cells; D008099:Liver / Q000166:cytology; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009173:Mycophenolic Acid / Q000737:chemistry / Q000378:metabolism; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism; D013552:Swine
D020719:Glucuronides; D009284:Naphthols; C029350:1-naphthol; D006923:Hymecromone; D004958:Estradiol; D009173:Mycophenolic Acid