Influence of tacrolimus on bile acid and lipid composition in continuously drained bile using a rat model. Comparative study with cyclosporine.
Cholestatic effects have been reported for cyclosporine (CsA), but information is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid composition 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 bile was continuously collected for the following 3 days. Bile flow, bile acid secretion rate (BASR), and biliary lipids secretion were measured for each of the groups. TCR increased bile acid-dependent flow (BADF) but with no statistical significance. However, this agent did not influence total bile flow and biliary lipids secretion, while bile acid-independent flow (BAIF) was significantly reduced and bile acid synthesis (mainly cholic acid, CA, synthesis) was increased. In contrast, CsA was cholestatic, showing a tendency to reduce both BADF and BAIF. BASR was dose-dependently suppressed, especially in chenodeoxycholic acid (CDCA). Furthermore, biliary lipids secretions were also significantly decreased under a higher dose of CsA. TCR increased BADF with no influence on total bile flow, having a stimulating effect on CA production, although CsA dose-dependently diminishes CDCA production and consequently reduced bile secretion. Our results suggest that TCR is a less effective agent on cholestasis as compared to CsA.
Mizuta
K
K
Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
Kobayashi
E
E
Uchida
H
H
Fujimura
A
A
Kawarasaki
H
H
Hashizume
K
K
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000032:analysis* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008055:Lipids / Q000032:analysis*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
D001647:Bile Acids and Salts; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine; D016559:Tacrolimus