THE EFFECT OF FK506 ON CANINE BILE-FLOW

While the primary immunosuppressive agents utilized in solid-organ transplantation are steroids and cyclosporine, the more recently introduced agent FK506 is assuming a progressively more important role as an immunosuppressant, particularly in liver transplantation. While the effect of cyclosporine on rat and canine bile flow has been well evaluated, no information is available regarding the effect of FK506 on bile flow. Dogs with chronic biliary fistulas were utilized, enabling unanesthetized animals to be studied. FK506 was administered intravenously in varying doses, and bile volume, bile salts, and bile electrolytes were measured. FK506 produced dose-related increases in bile volume and bile chloride concentration and output, with 8 mu g/kg(-1)hr(-1) being the maximal dose. To ascertain that the response was not osmotic in association with FK506 secretion in bile, 500 mu g/kg(-1)hr(-1) FK506 was administered, which did not produce a choleresis significantly greater than 8 mu g/kg(-1)hr(-1). FK506 was subsequently administered orally in daily dose of 0.15 mg/kg(-1) for two weeks. Oral FK506 did not consistently increase bile flow, as evaluated by a bile salt dose-response curve (9, 18, 36 mu mol/min sodium taurocholate) but did significantly increase bile chloride secretion. Two weeks of oral administration of FK506 in therapeutic doses did not significantly alter serum bile salt concentrations, The results of this study indicate that intravenous FK506 produces a chloride-rich choleresis in dogs.