Comparative study analyzing effects of sirolimus-cyclosporin and sirolimus-tacrolimus combinations on bile flow in the rat.
The new immunosuppressive agent sirolimus is combined in transplant patients with the cholestatic substances cyclosporin and tacrolimus. Nothing is known about possible cholestatic effects of these combinations. Therefore, we compared their effects on bile flow and on important bile parameters in an acute bile fistula model in rats. Cyclosporin reduced bile flow, biliary excretion of bile salts, cholesterol, and GSH to 20-40% of basal values. Sirolimus decreased bile flow to 50% and excretion of GSH to 30% of the initial conditions but had no effect on cholesterol and bile salt excretion. In contrast, tacrolimus increased bile flow to 120% and GSH excretion to 220% of the basal levels. Sirolimus/cyclosporin decreased bile flow and bile parameters to the same extent as cyclosporin alone. Sirolimus/tacrolimus reversed sirolimus-induced reduction of bile flow and GSH excretion and resulted in a normal bile salt and cholesterol excretion, thus it may be the better alternative in cholestatic patients.
Deters
M
M
Institute of Pharmacology, Medical School, Hannover, Germany.
Nolte
K
K
Kirchner
G
G
Resch
K
K
Kaever
V
V
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001658:Biliary Fistula / Q000503:physiopathology; D001659:Biliary Tract / Q000187:drug effects*; D002779:Cholestasis / Q000188:drug therapy; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use
D001647:Bile Acids and Salts; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus