Ursodeoxycholic acid–induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis

Abstract

Ursodeoxycholic acid treatment of patients with primary biliary cirrhosis may lead to relief of pruritus and improvement of biochemical liver tests. The changes in serum and urinary bile acids induced by ursodeoxycholic acid treatment were studied. After 29 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (750 to 1,000 mg/day) for 6 to 12 mo because of an increase in ursodeoxycholic acid, total plasma bile acids increased from 30.5 +/- 6 mumol/L (mean +/- S.E.M.) to 52.7 +/- 11.7 mumol/L (p less than 0.01). The increase in total plasma bile acids correlated significantly with concentrations of plasma bile acid before treatment (p less than 0.01). The concentrations of endogenous bile acids decreased, mainly because of a decrease of cholic acid. During treatment, glycine conjugation increased and taurine conjugation decreased, whereas sulfation and glucuronidation of bile acids were unchanged. In 10 patients with primary biliary cirrhosis in stages III and IV, urinary excretion of bile acids was also studied. After treatment, ursodeoxycholic acid and its 3-beta isomer and C-1-hydroxylated and C-6-hydroxylated derivatives were also excreted. During treatment, urinary excretion of endogenous bile acids decreased. The increase of ursodeoxycholic acid and the decrease of endogenous bile acids may both be related to the improvement of biochemical liver tests in precirrhotic stages of the disease. In cirrhosis, endogenous bile acids in plasma remained high and changes in liver tests were small.

Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis

“…38 Therefore, it can be speculated that cholestasis may initiate alternative metabolic pathways leading to these atypical compounds. It is unlikely that this fraction derives from previous UDCA therapy for three reasons: first, these compounds are different from the metabolites of UDCA reported in other studies 39,40 ; second, this fraction dramatically decreased during the administration of both UDCA and TUDCA; and, finally, a similar amount of unusual bile acids was also found in the three patients who had never received UDCA or TUDCA before the study. This heterogeneous fraction, also containing several highly hydrophobic metabolites, was proportionally reduced to a greater extent by TUDCA administration than with UDCA.…”

“…hydroxy, 6␣-hydroxy and the partial side-chain oxidized unsaturated metabolite, ⌬ 22 -UDCA, and have been previously identified as specific metabolites of UDCA. [39][40][41][42][43] The reduced biotransformation of TUDCA may be explained in terms of the protection of the molecule afforded by the presence of the amino acid in the side-chain. 44 As expected, TUDCA was not completely resistant to biotransformation during enterohepatic recycling, because deconjugation of the bile acid, followed by reconjugation with glycine, presumably accounts for the increase in glycine-conjugated UDCA in duodenal fluid during treatment.…”

A paucity of unusual trihydroxy bile acids in the urine of patients with severe liver diseases

“…Even the three individuals who did not have unusual trihydroxy bile acids in urine before UDCA treatment, had detectable levels of these bile acids on the fourth day of UDCA treatment. The induction of unusual trihydroxy bile acids by UDCA treatment was previously reported in patients with primary biliary cirrhosis 16,17 but the improvement of liver function with long-term UDCA therapy is assumed to play a part in the appearance of these bile acids in the reported cases. The present study revealed, for the first time, that UDCA treatment for 3 days is adequate for assessing bile acid-hydroxylation in the liver.…”

Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune hepatitis: A randomized placebo-controlled treatment trial

“…Consequently, we cannot exclude the possibility that inadequate drug absorption or bile enrichment diminished its efficacy. Such studies, however, have been performed in chronic hepatitis 12,29 and PBC, [30][31][32] and these deficiencies have not been encountered, even in individuals receiving lower doses of ursodeoxycholic acid than those administered in our study. Based on these experiences, we had no reason to assume unprecedented deficiencies in absorption as a basis for our discouraging results.…”