A side chain derivative of
ursodeoxycholic acid,
23-methylursodeoxycholic acid, was synthesized and the effect of i.v. infusion of the
acid at different doses (0.75, 1.5, 3.0 and 6.0 mumoles per min per kg
body weight over 1 hr) on bile flow, on its hepatic biotransformations and on biliary
lipid secretion has been studied in bile
fistula rats. The results were compared with those of ursodeoxycholic and
cholic acid administered under similar conditions.
23-Methylursodeoxycholic acid is poorly secreted into bile and poorly
taurine and
glycine conjugated, at all infusion doses.
Ursodeoxycholic acid is quantitatively recovered at low doses and recovered less at high infusion rates.
Cholic acid is almost entirely recovered at all infusion doses.
Ursodeoxycholic acid conjugation pattern is dependent on the dose, and glucuronidation and sulfation operate at high doses.
Cholic acid is
taurine conjugated at low doses; at high doses, large amounts of unconjugated
bile acids are observed. Methylursodeoxycholic
acid presents a delayed secretion and hypercholeresis.
Ursodeoxycholic acid presents similar results at high infusion rates, possibly by reaching a high intrahepatic concentration of free form. The octanol/water partition coefficients of
ursodeoxycholic acid and
23-methylursodeoxycholic acid are similar and higher than that of
cholic acid. A chole-hepatic shunting of
23-methylursodeoxycholic acid may explain both the low recovery in bile and hypercholeresis and is consistent with its hydrophilicity of
cholic acid, on the contrary, makes possible its high recovery in bile. The effect on biliary
lipid secretion is unpredictable and affected by the dose and, in consequence, by the conjugation pattern of the
bile acid.(ABSTRACT TRUNCATED AT 250 WORDS)