Improvement of estradiol-17 beta-D-glucuronide-induced cholestasis by sodium tauroursodeoxycholate therapy in rats.
BACKGROUND
Estradiol-17 beta-D-glucuronide (E-17G), a metabolite of natural estrogen, is well known to cause intrahepatic cholestasis in humans. We therefore investigated the effect of sodium tauroursodeoxycholate (T-UDCA), on E-17G-induced cholestasis in female rats.


METHODS
For the evaluation of the drug, animals given E-17G (10 mumol/kg) were divided into three groups, and T-UDCA was administered intravenously at various doses after E-17G treatment.


RESULTS
T-UDCA significantly prevented a marked reduction of bile flow in E-17G-treated rats in all experimental schedules. Furthermore, T-UDCA significantly increased in the biliary E-17G excretion rate at an early stage after E-17G treatment in rats. However, this drug caused no significant change in the biliary excretion rate of estradiol-3-sulfate-17 beta-D-glucuronide (E-3S-17G), which is identified as the major biliary metabolite with E-17G throughout the recovery periods.


CONCLUSIONS
These results suggest that T-UDCA can improve E-17G induced acute cholestasis by rapidly increasing the biliary E-17G excretion rate. Thus our finding may provide a useful approach for attempts to prevent drug-induced acute cholestasis in humans.
Kinbara
S
S
Pharmacological Research Laboratory, Tokyo Tanabe Co. Ltd., Japan.
Ishizaki
K
K
Sakakura
H
H
Hirabayashi
N
N
Kasai
H
H
Araki
T
T
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy*; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000627:therapeutic use*; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
D001647:Bile Acids and Salts; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid