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Metabolism of Bile Acids. XIV. Sarcosine Conjugated Bile Acids

1984; Pharmaceutical Society of Japan; Volume: 104; Issue: 5 Linguagem: Inglês

10.1248/yakushi1947.104.5_466

1347-5231

Shunso Hatono, YOKO HIRONAKA, Taiju Kuramoto, Takahiko Hoshita,

Drug Solubulity and Delivery Systems

In order to develop new cholelitholytic agents, sarcosine conjugated chenodeoxycholic acid (SCDC) and ursodeoxycholic acid (SUDC) were synthesized. The effect of oral administration of SCDC and SUDC on the formation of gallstones was studied in a mouse model of cholesterol cholelithiasis. Groups were fed a lithogenic diet with or without the sarcosine-conjugated bile acids for 12 weeks. Cholesterol gallstones formed in 100% of the animals fed a lithogenic diet, 75% of those fed 0.03% of SCDC and SUDC, and 35% and 15% of those fed 0.15% of SCDC and SUDC, respectively. Acute toxicity studies show that the LD50 of SCDC and SUDC for the mice administered orally were 3750 mg/kg and >10000 mg/kg, respectively. Intestinal absorption studies using bile fistula rats show that more than 90% of both the sarcosine-conjugated bile acids administered intraduodenally were excreted in the bile within 24 h. No changes of the administered bile acids were seen during the absorption from the intestine, the passage of the liver, and the excretion into the bile. Studies of enzymatic hydrolysis with cholyglycine hydrolase of SCDC and SUDC show that the sarcosine-conjugated bile acids were not hydrolysed at all within 120 min, while glycine-conjugated bile acids were hydrolysed completely.