UGT-dependent regioselective glucuronidation of ursodeoxycholic acid and obeticholic acid and selective transport of the consequent acyl glucuronides by OATP1B1 and 1B3.

Ursodeoxycholic acid (UDCA) is a major effective constituent of bear bile powder, which is widely used as function food in China and is documented in the Chinese pharmacopoeia as a traditional Chinese medicine. UDCA has been developed as the only accepted therapy by the US FDA for primary biliary cholangitis. Recently, the US FDA granted accelerated approval to obeticholic acid (OCA), a semisynthetic bile acid derivative from chenodeoxycholic acid, for primary biliary cholangitis. However, some perplexing toxicities of UDCA have been reported in the clinic. The present work aimed to investigate the difference between UDCA and OCA in regard to potential metabolic activation through acyl glucuronidation and hepatic accumulation of consequent acyl glucuronides. Our results demonstrated that the metabolic fates of UDCA and OCA were similar. Both UDCA and OCA were predominantly metabolically activated by conjugation to the acyl glucuronide in human liver microsomes. UGT1A3 played a predominant role in the carboxyl glucuronidation of both UDCA and OCA, while UGT2B7 played a major role in their hydroxyl glucuronidation. Further uptake studies revealed that OATP1B1- and 1B3-transfected cells could selectively uptake UDCA acyl glucuronide, but not UDCA, OCA, and OCA acyl glucuronide. In summary, the liver disposition of OCA is different from that of UDCA due to hepatic uptake, and liver accumulation of UDCA acyl glucuronide might be related to the perplexing toxicities of UDCA.

Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors.

Cisplatin-bile acid derivatives belonging to the Bamet-family maintain both liver organotropism and cytostatic activity. "In vivo" toxicity and usefulness as chemotherapeutic agent versus liver tumors of a novel drug, Bamet-UD2 [cis-diamminechlorocholylglycinate platinum (II)], with enhanced "in vitro" cytostatic activity was investigated. Using orthotopically implanted mouse Hepa 1-6 hepatoma in the liver of Nude mice, the antitumor effect of Bamet-UD2 was compared with that of a previously characterized compound of this family, Bamet-R2 [cis-diamminebis-ursodeoxycholate platinum(II)], and cisplatin. Life span was significantly prolonged in mice treated with both Bamets (Bamet-UD2 > Bamet-R2), compared with animals receiving saline or cisplatin. All these drugs inhibit tumor growth (Bamet-UD2 = cisplatin > Bamet-R2). However, toxicity-related deaths only occurred under cisplatin treatment. Using rats maintained in metabolic cages, organ-specific toxicity and drug accumulation in tissues were investigated. The amount of both Bamets in the liver was severalfold higher than that of cisplatin. By contrast, a significantly higher amount of cisplatin in kidney and nerve was found. In lung, heart, muscle, brain, and bone marrow the amount of drug was small and also significantly lower in animals receiving Bamets. Signs of neurotoxicity (altered nerve conduction velocity), nephrotoxicity (increased serum urea and creatinine concentrations and decreased creatinine clearance), and bone marrow toxicity (decreased platelet and white blood counts) in animals treated with cisplatin but not with the Bamets were found. These results indicate that, owing to strong antitumor activity together with absence of side effects, Bamet-UD2 may be useful in the treatment of liver tumors.

Effects of chenodeoxycholic and ursodeoxycholic acids on lipid metabolism and gallstone formation in the prairie dog.

The prevention of cholesterol cholelithiasis by dietary chenodeoxycholic and ursodeoxycholic acids was studied in the male prairie dog (Cynomys ludovicianus). Gallstones were induced by administration of a semisynthetic diet containing 0.4% cholesterol for a period of 8 weeks. Groups of 5 or 6 animals received the lithogenic diet with added chenodeoxycholic or ursodeoxycholic acid (0.03% "low dose" or 0.06% "high dose"). Under the conditions used, the incidence of gallstones was reduced with the high dose of chenodeoxycholic acid and the low dose of ursodeoxycholic acid, but cholesterol crystals were detected in the biles of 20 of the 22 animals fed these bile acids. A control group maintained on a low (0.08%) cholesterol semisynthetic diet exhibited neither crystals nor stones and was the only group with a lithogenic index below 1.0. The administered bile acids tended to reduce the accumulation of cholesterol in liver and plasma. The activity of hepatic HMG-CoA reductase was significantly inhibited with all cholesterol-supplemented diets. Cholesterol 7 alpha-hydroxylase activity was elevated 83% in prairie dogs fed 0.4% cholesterol, but tended to return to normal levels when bile acids were added to this diet. Histologically, the livers of all animals on the semisynthetic (cholesterol-supplemented) diet exhibited bile duct proliferation, as well as portal fibrosis and inflammatory infiltration. These morphologic alterations were ameliorated by low dose supplementation with either chenodeoxycholic or ursodeoxycholic acid, but high dose bile acid supplementation failed to reduce these pathologic changes.