Hepatic clearance and biliary secretory rate maximum of taurocholate in the recirculating and single pass isolated perfused rat liver. Effects of the cholestatic agent, estradiol-17 beta- (beta-D-glucuronide)

Vore, M.; Durham, S.; Yeh, S.; Ganguly, T.

Biochemical Pharmacology 41(3): 431-437

1991


ISSN/ISBN: 0006-2952
PMID: 1994901
Accession: 007394215

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Abstract
The ability of the cholestatic steroid glucuronide, estradiol-17.beta.-(.beta.-D-glucuronide) (E217G), to inhibit the hepatic clearance (ClH) and biliary secretory rate maximum (SRm) of taurocholate was investigated in the recirculating and single pass isolated perfused male rat liver. In the recirculating perfused liver, E217G (0, 2, 4, or 6 .mu.mol) was added as a bolus dose to the reservoir at zero time while taurocholate was infused into the portal vein in increasing amounts (15, 30, 45, or 60 .mu.mol/mL; 1 mL/hr for 15 min each). E217G (4 .mu.mol) caused a significant (P < 0.05) inhibition of bile flow and bile acid secretion at 10-15 min during infusion of 15 .mu.mol/hr taurocholate but did not inhibit the SRm which occurred at 42 min, indicating that E217G had not caused an irreversible inhibition of taurocholate transport. E217G (6 .mu.mol) caused a profound and irreversible inhibition of bile flow attributable to retention of E217G in the liver. The noncholestatic estradiol-3-(.beta.-D-glucuronide) (E23G; 6 .mu.mol) had no significant effect on bile flow or the SRm. In the single pass perfused liver (10 mL/min flow rate), E217G (0, 1, 2, 5, or 10 nmol/mL) or E23G (2 nmol/mL) was added to the perfusate resulting in a stable infusion to the liver. [3H]Taurocholate was infused into the portal vein in increasing amounts to give inflow concentrations (Cin) of 25, 50, 75 or 100 nmol/mL. In the absence of E217G, taurocholate ClH decreased from 0.92 to 0.70 mL/min/g liver with increasing taurocholate concentrations. Neither E217G nor E23G altered the ClH of 25 nmol/mL taurocholate. E217G (10 nmol/mL) inhibited bile flow and bile acid secretion first at 20-25 min, followed by inhibition of ClH of 75 and 100 nmol/mL taurocholate (35-60 min). In contrast, E23G stimulated bile acid secretion and increased the SRm by 80%. Thus, at doses that did not block its own elimination, E217G did not cause an irreversible inhibition of taurocholate transport into bile. E217G did not directly inhibit the uptake of taurocholate into the liver but first inhibited the biliary excretion of taurocholate, resulting in its intrahepatic accumulation and decreased clearance from the perfusate.