Influence of tacrolimus on bile acid and lipid composition in continuouslydrained bile using a rat model - Comparative study with cyclosporine

Cholestatic effects have been reported for cyclosporine (CsA), but informat ion is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid compositio n as compared with CsA, using a continuously bile-drained rat model. Adult male Wistar rats received TCR (0.4 mg/kg, 1 mg/kg, and 4 mg/kg) or CsA (2.5 mg/kg, 10 mg/kg, and 25 mg/kg) by intramuscular injection (i.m.) daily for 10 days,On day 7, the common bile duct of all rats was cannulated, then bi le was continuously collected for the following 3 days. Bile flow, bile aci d secretion rate (BASR), and biliary lipids secretion were measured for eac h of the groups. TCR increased bile acid-dependent flow (BADF) but with no statistical significance. However this agent did not influence total bile f low and biliary lipids secretion, while bile acid-independent flow (BAIF) w as significantly reduced and bile acid synthesis (mainly cholic acid, CA, s ynthesis) was increased. In contrast, CsA was cholestatic, showing a tenden cy to reduce both BADF and BAIF. BASR was dose-dependently suppressed, espe cially in chenodeoxycholic acid (CDCA). Furthermore biliary lipids secretio ns were also significantly decreased under a higher dose of CsA, TCR increa sed BADF with no influence on total bile Row, having a stimulating effect o n CA production, although CsA dose-dependently diminishes CDCA production a nd consequently reduced bile secretion. Our results suggest that TCR is a l ess effective agent on cholestasis as compared to CsA.