Estradiol-17 beta-D-glucuronide (E-17G) cholestasis in perfused rat liver: fate of E-17G and choleretic responses to bile salts.
This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug-induced cholestasis. Cholestasis was induced by administration of 17.5 mumol/L estradiol-17 beta-D-glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 mumol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose-dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose-dependent recovery. Further increase of tauroursodeoxycholate infusion rate of 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradiol-17 beta-D-glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol-17 beta-D-glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol-17 beta-D-glucuronide declined significantly, and a marked back-efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol-17 beta-D-glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back-efflux of estradiol-17 beta-D-glucuronide at the two highest tauroursodeoxycholate infusion rates.(ABSTRACT TRUNCATED AT 250 WORDS)
Utili
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Institute of Medical Therapy, First Medical School, Naples, Italy.
Tripodi
M F
MF
Adinolfi
L E
LE
Gaeta
G B
GB
Abernathy
C O
CO
Zimmerman
H J
HJ
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001692:Biological Transport; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism; D003685:Dehydrocholic Acid / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013395:Sucrose / Q000493:pharmacokinetics; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013656:Taurocholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D013655:Taurochenodeoxycholic Acid; D013395:Sucrose; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D003685:Dehydrocholic Acid