Hypercholeresis induced by unconjugated bile acid infusion correlates with recovery in bile of unconjugated bile acids

Abstract

Using the isolated perfused rat and hamster liver, the relationship between bile flow, bile acid secretion rate and bile acid biotransformation after the injection of a small, bolus dose of radioactive ursodeoxycholate or of its C23 homolog, norursodeoxycholate, was examined. Ursodeoxycholate was promptly secreted into bile mostly as amino acid conjugates; less than 3% was secreted in unchanged form in the rat and less than 2% in the hamster. In contrast, norursodeoxycholate was secreted slowly, and biotransformed into glucuronide conjugates and unconjugated trihydroxy derivatives; it was also secreted in part in unchanged form. In the rat, 7% was secreted in unconjugated trihydroxy derivatives and 3% in unchanged form; in the hamster, 7% was secreted as unconjugated trihydroxy derivatives and 4% in unchanged form. The secreted bile acid species that showed the highest correlation with bile flow by far was always the unconjugated form in both rat and hamster. By multiple regression analysis, the apparent choleretic activity (microliters of induced bile flow per micromoles recovered bile acid molecules) indicated marked hypercholeresis for the unconjugated bile acid marked hypercholeresis for the unconjugated bile acid with values ranging from 100 to 300 microliters/mumol. Bile flow also correlated with total bile acid recovery for ursodeoxycholate in rat and norursodeoxycholate in hamster, but in all studies the apparent choleretic activity was far lower. Other calculations indicated that most bile flow during the first 30 min was induced by secretion of the unconjugated bile acid species in all experiments, the proportion ranging from 50% to 90%. The results indicate that when a bolus of ursodeoxycholate or norursodeoxycholate is presented to the perfused rodent liver, the secretion of the unchanged bile acid appears to be responsible for most of the bile flow, probably by a cholehepatic shunting mechanism.

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

“…One possibility is that the ASBT functions in the cholehepatic shunt pathway. The term cholehepatic shunt was originally coined by Alan Hofmann to describe the cycle whereby unconjugated dihydroxy bile acids secreted into bile are passively absorbed by the epithelial cells (cholangiocytes) lining the bile ducts, returned to the hepatocyte via the periductular capillary plexus, and resecreted into bile (Gurantz et al 1991). Absorption of the protonated unconjugated bile acid molecule generates a bicarbonate anion, resulting in a bicarbonate-rich choleresis.…”

.DELTA.22-Ursodeoxycholic Acid, a Unique Metabolite of Administered Ursodeoxycholic Acid in Rats, Indicating Partial .beta.-Oxidation as a Major Pathway for Bile Acid Metabolism

“…Nevertheless, the Sprague-Dawley rat is a useful animal model for bile acid studies. UDCA has a potent hypercholeretic effect (Lake et al, 1987; Gurantz et al, 1991) in the rat, and during its enterohepatic recycling it is efficiently biotransformed, most notably by conjugation with taurine. In studies of the metabolism and physiological effects of a number of analogues of UDCA, we consistently observed a quantitatively important metabolite of UDCA, which we have now established to be A"-UDCA (Setchell et al, 1993).…”

Bile Formation and the Enterohepatic Circulation

“…181 Absorption of the protonated unconjugated bile acid molecule generates a bicarbonate anion, resulting in a bicarbonate-rich choleresis. 181 Absorption of the protonated unconjugated bile acid molecule generates a bicarbonate anion, resulting in a bicarbonate-rich choleresis.…”