Studies on toxicity and pharmacokinetics of the synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile.
The tripeptide-type synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine nitrile (1) was studied with respect to its toxicity and pharmacokinetics in mice, rats and rabbits. In mice the LD50 after i.v. injection was determined to be about 30-40 mg/kg. After i.v. injection and infusion in rats 1 caused a decrease in blood pressure up to 70-80% of initial values. The dose of 2 mg/kg.min led to a final outcome after about 15 min accompanied by a sharp decrease in blood pressure. The bleeding time after standardized incision of the rat tail was not significantly prolonged at doses which were tolerated. In pharmacokinetic studies the biologic half-life of 1 after i.v. injection was estimated to be about 12 min. After s.c. injection measurable plasma levels were obtained up to 5 h. Oral or intraduodenal administration of high doses of the inhibitor did not give effective plasma levels. Biliary excretion seems to be an important route of elimination. Cumulative excretion of 1 with the bile amounted to 31% of the dose within 240 min.
Kaiser
B
B
Institute of Pharmacology and Toxicology, Medical Academy Erfurt.
Hauptmann
J
J
Markwardt
F
F
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D004386:Duodenum; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013917:Thrombin / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; C055799:phenylalanyl-prolyl-arginine nitrile; D013917:Thrombin