INFLUENCE OF INDOCYANINE GREEN ON PLASMA DISAPPEARANCE AND BILIARY-EXCRETION OF A SYNTHETIC THROMBIN INHIBITOR OF THE 3-AMIDINOPHENYLALANINE PIPERAZIDE-TYPE IN RATS

Purpose, The pharmacokinetics of a number of synthetic peptidomimetic thrombin inhibitors is determined by extensive hepatic elimination. Th e objective was to further characterize the disposition in vivo of Pef a 1023, a novel 3-amidinophenylalanine piperazide-type thrombin inhibi tor, by influencing the hepatic handling with indocyanine green (ICG), which is actively taken up by the liver. Methods. Pefa 1023 was admin istered intravenously to bile duct-cannulated rats, either alone or in combination with ICG. The concentrations of Pefa 1023 in blood plasma and bile were measured by a bioassay (thrombin clotting time), concen trations of indocyanine green were measured spectrophotometrically. Re sults. ICG (10 mg/kg i.v. 15 min prior to or simultaneously with Pefa 1023) markedly influenced the plasma level and biliary excretion rate of the thrombin inhibitor Pefa 1023 given in a dose of 1 mg/kg i.v. Th e plasma level was more than twice that of the control, the maximum bi liary excretion rate about one third and the fraction of dose excreted in bile about two thirds. Conclusions. The anionic dye ICG is able to interfere with the hepatic handling of a cationic, amidinophenylalani ne piperazide-type thrombin inhibitor with the consequence of reduced hepatic clearance leading to higher plasma levels and lower biliary ex cretion of the latter.