The effects of the phytoestrogenic isoflavone genistein on the hepatic disposition of preformed and hepatically generated gemfibrozil 1-O-acyl glucuronide in the isolated perfused rat liver.
Foods and complementary medicines contain phytoestrogenic isoflavones such as genistein, which undergo hepatic glucuronidation and excretion into bile and can potentially interfere with the hepatic elimination of other compounds. To investigate this potential, livers from Sprague-Dawley rats were perfused in single-pass mode with preformed gemfibrozil 1-O-acyl glucuronide (GG) (1 microM, n = 12) for 60 min followed by a 30-min washout phase, or with gemfibrozil (1 microM, n = 10) for 120 min. Half of each group of livers were co-perfused with genistein (10 microM) throughout the experiment. Perfusate and bile were analyzed for GG and gemfibrozil by HPLC. Co-perfusion with genistein significantly (P< 0.05) decreased the biliary extraction ratio of preformed GG from a mean of 0.82 to 0.65 and the first-order rate constant for transport of GG into bile from 0.054 +/- 0.010 to 0.032 +/- 0.008 min(-1), but increased the first-order rate constant for sinusoidal efflux of GG from 0.128 +/- 0.023 to 0.227 +/- 0.078 min(-1). Co-perfusion with genistein also significantly decreased the biliary extraction ratio of hepatically generated GG from 0.95 +/- 0.01 to 0.83 +/- 0.05. The findings confirm that genistein increases the potential for hepatic and systemic exposure to hepatically generated glucuronides, which may be important for patients on conventional drugs who consume isoflavones.
Lucas
Anthony N
AN
Centre for Pharmaceutical Research, School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, SA 5000, Australia.
Brogan
Léonie R
LR
Nation
Roger L
RL
Milne
Robert W
RW
Evans
Allan M
AM
Shackleford
David M
DM
D000818:Animals; D010478:Chemotherapy, Cancer, Regional Perfusion; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015248:Gemfibrozil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D019833:Genistein / Q000494:pharmacology*; D005965:Glucuronates / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000737:chemistry; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D005965:Glucuronates; C094370:gemfibrozil 1-O-acylglucuronide; D019833:Genistein; D015248:Gemfibrozil