Influence of indocyanine green on plasma disappearance and biliary excretion of a synthetic thrombin inhibitor of the 3-amidinophenyl-alanine piperazide-type in rats.
OBJECTIVE
The pharmacokinetics of a number of synthetic peptidomimetic thrombin inhibitors is determined by extensive hepatic elimination. The objective was to further characterize the disposition in vivo of Pefa 1023, a novel 3-amidinophenylalanine piperazide-type thrombin inhibitor, by influencing the hepatic handling with indocyanine green (ICG), which is actively taken up by the liver.


METHODS
Pefa 1023 was administered 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), concentrations of indocyanine green were measured spectrophotometrically.


RESULTS
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. The plasma level was more than twice that of the control, the maximum biliary 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, amidinophenylalanine piperazide-type thrombin inhibitor with the consequence of reduced hepatic clearance leading to higher plasma levels and lower biliary excretion of the latter.
Hauptmann
J
J
Zentrum für Vaskuläre Biologie und Medizin, Klinikum der Friedrich-Schiller-Universität Jena, Erfurt, Germany. hauptman@zmhk.ef.uni-jena.de
Stürzebecher
J
J
D000704:Analysis of Variance; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004396:Coloring Agents / Q000494:pharmacology*; D005260:Female; D007208:Indocyanine Green / Q000494:pharmacology*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D018716:Molecular Mimicry; D010880:Piperidines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000037:antagonists & inhibitors*
D004396:Coloring Agents; D010880:Piperidines; D013917:Thrombin; D007208:Indocyanine Green