Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) exerts anticholestatic, antifibrotic and antiproliferative effects in primary biliary cirrhosis (PBC) via mechanisms not yet fully understood. Its adequate biliary enrichment is considered mandatory for therapeutic efficacy. However, precise determination of biliary enrichment of UDCA is not possible in clinical practice. Therefore, we investigated (i) the relationship between biliary enrichment and plasma pharmacokinetics of UDCA, (ii) the effect of UDCA on plasma and biliary bile acid composition and conjugation patterns, and (iii) on the intestinal detoxification machinery in patients with PBC and healthy controls. METHODS: In 11 PBC patients and 11 matched healthy subjects, cystic bile and duodenal tissue were collected before and after 3 weeks of administration of UDCA (15 mg/kg/day). Extensive pharmacokinetic profiling of bile acids was performed. The effect of UDCA on the intestinal detoxification machinery was studied by quantitative PCR and Western blotting. RESULTS: The relative fraction of UDCA and its conjugates in plasma at trough level[x] correlated with their biliary enrichment[y] (r=0.73, p=0.0001, y=3.65+0.49x). Taurine conjugates of the major hydrophobic bile acid, chenodeoxycholic acid, were more prominent in bile of PBC patients than in that of healthy controls. Biliary bile acid conjugation patterns normalized after treatment with UDCA. UDCA induced duodenal expression of key export pumps, BCRP and P-glycoprotein. CONCLUSIONS: Biliary and trough plasma enrichment of UDCA are closely correlated in PBC and health. Taurine conjugation may represent an adaptive mechanism in PBC against chenodeoxycholic acid-mediated bile duct damage. UDCA may stabilize small intestinal detoxification by upregulation of efflux pumps.

Pseudohypocalcemia caused by perchlorate (Irenat).

BACKGROUND: Blood gas analysis (BGA), including measurement of ionized calcium, is performed routinely in patients with end stage renal disease on renal replacement therapy, especially when using citrate for regional anticoagulation. After installation of a new blood gas analyzer (RAPIDpoint 405; BGA), we observed lower ionized calcium concentrations in a few patients without signs of hypocalcemia, whereas calcium concentrations were normal using a standard laboratory method. Pseudohypocalcemia was of limited duration and correlated with the short-term intake of sodium perchlorate monohydrate (Irenat). METHODS: We prepared dilution series from whole blood samples and stock solutions of calcium and perchlorate with different concentrations of ionized calcium and perchlorate. Measurement of ionized calcium concentrations was performed using two different blood gas analyzers (RAPIDpoint 405; BGA and Roche AVL 9180; standard laboratory method). RESULTS: After addition of different amounts of perchlorate, significant lower ionized calcium concentrations were measured with BGA compared to the standard laboratory method using either preparations from whole blood samples or stock solutions. The addition of potassium or methylene blue known to complex perchlorate had no effect on the concentrations of ionized calcium measured with BGA. Using different mathematical methods, a calculation of the "real" ionized calcium concentration from the value measured with BGA was not possible. CONCLUSIONS: Based on our experiments, we confirm the hypothesis that perchlorate can influence the measurement of ionized calcium by BGA. As the effect depends on the ion selective electrode that is used, it is advisable to test the blood gas analyzer with calcium and perchlorate solutions.