Inhibition of leukotriene uptake by cyclosporine

1. The isolated perfused rat liver efficiently takes up cysteinyl leukotrienes (LTs) C4, D4, E4 and N-acetylLTE4 from circulation. More than 70 of these cysteinyl LTs are excreted from liver into bile within I h of onset of a 5 min infusion, while about 5 remain in the liver. About 20 of infused N-acetyl-LTE4 escapes hepatic first-pass extraction under our conditions. 2. Metabolites of LTC4 appearing in bile within 20 min of the onset of infusion include mainly LTD4 and N-acetyl-LTE4, but also w-hydroxy-N-acetylLTE4 and o-carboxy-N-acetyl-LTE4. Metabolites generated from w-carboxy-N-acetyl-LTE4 by fl-oxidation from the w-end represent the major biliary LTs secreted at later times. 3. Stimulation of the isolated perfused liver by the combined infusion of the phorbol ester 12-O-tetradecanoylphorbol13-acetate (TPA) and the Ca2l ionophore A23187 results in a transient increase of endogenous cysteinyl LT production, which is independent of extrahepatic cells. 4. The immunosuppressive drug cyclosporine causes a dose-dependent inhibition of hepatobiliary cysteinyl LT excretion, probably by interference with the sinusoidal uptake system for cysteinyl LTs.