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Title: In vivo studies of a synthetic inhibitor of thrombin

Abstract

The kinetics and the turnover and anticoagulant action in rabbits were studied of D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone (D-Phe-Pro-Arg-Ch/sub 2/Cl) (FPRMeCl), a synthetic irreversible inhibitor of thrombin. The inhibition of thrombin by FPRMeCl could be described as a two-step reaction; a reversible complex formation with a Klt. slashsub jlt. slash of 3.7 x 10/sup -8/M followed by formation of an irreversible complex with a rate constant k/sub 2/ of 0.4 sec/sup -1/. The disappearance rate from the plasma in six rabbits after intravenous injection of 1 mg of FPRMeCl could be described by a sum of two exponential terms, the first with a half-life of 0.7 min and the second with a half-life of 2.9 min. The recovery of inhibitory activity in the urine in two rabbits was 2.3% and 5.4%. After subcutaneous injection of 1 mg in six rabbits, the FPRMeCl level in plasma rose to an average value of 1 ..mu..M after 10 min and decreased gradually to 50 nM after 90 min. Intravenous injection of 0.5 mg human thrombin over 5 min in seven anesthesized rabbits resulted in death due to massive thrombosis in the right heart. Six rabbits that had received an intravenous injection of 1 mg of FPRMeClmore » just before the thrombin infusion all survived without a significant drop in fibrinogen levels. Infusion of 12 ml of a brain thromboplastin suspension over 30 min in six rabbits resulted in extensive prothrombin activation (residual prothrombin 21% +/- 1.5 of preinfusion value) and virtually complete defibrination (residual fibrinogen 14% +/- 4). Subcutaneous injection of 1 mg of FPRMeCl before and 30 to 60 min after the start of the thromboplastin infusion in four rabbits resulted in a comparable degree of prothrombin activation and a decrease of the fibrinogen level to 30% +/- 5 of its preinfusion level.« less

Authors:
 [1]; ; ; ;
  1. Univ. of Leuren, Belgium
Publication Date:
OSTI Identifier:
5761434
Resource Type:
Journal Article
Journal Name:
J. Lab. Clin. Med.; (United States)
Additional Journal Information:
Journal Volume: 99:1
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ENZYME INHIBITORS; BIOCHEMICAL REACTION KINETICS; THROMBIN; INHIBITION; ALKYLATION; COMPLEXES; ENZYMES; EXPERIMENTAL DATA; FIBRINOGEN; IN VIVO; KETONES; RABBITS; ANIMALS; BLOOD COAGULATION FACTORS; CHEMICAL REACTIONS; COAGULANTS; DATA; DRUGS; GLOBULINS; HEMATOLOGIC AGENTS; HEMOSTATICS; HYDROLASES; INFORMATION; KINETICS; MAMMALS; NUMERICAL DATA; ORGANIC COMPOUNDS; PEPTIDE HYDROLASES; PROTEINS; REACTION KINETICS; SERINE PROTEINASES; VERTEBRATES; 550200* - Biochemistry; 551000 - Physiological Systems

Citation Formats

Collen, D, Matsuo, O, Stassen, J M, Kettner, C, and Shaw, E. In vivo studies of a synthetic inhibitor of thrombin. United States: N. p., 1982. Web.
Collen, D, Matsuo, O, Stassen, J M, Kettner, C, & Shaw, E. In vivo studies of a synthetic inhibitor of thrombin. United States.
Collen, D, Matsuo, O, Stassen, J M, Kettner, C, and Shaw, E. 1982. "In vivo studies of a synthetic inhibitor of thrombin". United States.
@article{osti_5761434,
title = {In vivo studies of a synthetic inhibitor of thrombin},
author = {Collen, D and Matsuo, O and Stassen, J M and Kettner, C and Shaw, E},
abstractNote = {The kinetics and the turnover and anticoagulant action in rabbits were studied of D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone (D-Phe-Pro-Arg-Ch/sub 2/Cl) (FPRMeCl), a synthetic irreversible inhibitor of thrombin. The inhibition of thrombin by FPRMeCl could be described as a two-step reaction; a reversible complex formation with a Klt. slashsub jlt. slash of 3.7 x 10/sup -8/M followed by formation of an irreversible complex with a rate constant k/sub 2/ of 0.4 sec/sup -1/. The disappearance rate from the plasma in six rabbits after intravenous injection of 1 mg of FPRMeCl could be described by a sum of two exponential terms, the first with a half-life of 0.7 min and the second with a half-life of 2.9 min. The recovery of inhibitory activity in the urine in two rabbits was 2.3% and 5.4%. After subcutaneous injection of 1 mg in six rabbits, the FPRMeCl level in plasma rose to an average value of 1 ..mu..M after 10 min and decreased gradually to 50 nM after 90 min. Intravenous injection of 0.5 mg human thrombin over 5 min in seven anesthesized rabbits resulted in death due to massive thrombosis in the right heart. Six rabbits that had received an intravenous injection of 1 mg of FPRMeCl just before the thrombin infusion all survived without a significant drop in fibrinogen levels. Infusion of 12 ml of a brain thromboplastin suspension over 30 min in six rabbits resulted in extensive prothrombin activation (residual prothrombin 21% +/- 1.5 of preinfusion value) and virtually complete defibrination (residual fibrinogen 14% +/- 4). Subcutaneous injection of 1 mg of FPRMeCl before and 30 to 60 min after the start of the thromboplastin infusion in four rabbits resulted in a comparable degree of prothrombin activation and a decrease of the fibrinogen level to 30% +/- 5 of its preinfusion level.},
doi = {},
url = {https://www.osti.gov/biblio/5761434}, journal = {J. Lab. Clin. Med.; (United States)},
number = ,
volume = 99:1,
place = {United States},
year = {1982},
month = {1}
}