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Title: Pharmacokinetics of activated protein C in guinea pigs

Abstract

Protein C is a vitamin K-dependent zymogen of the serine protease, activated protein C (APC), an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the pharmacokinetics and tissue distribution of APC were studied in guinea pigs. The plasma elimination of a trace dose of {sup 125}I-APC was biphasic following an initial rapid elimination of approximately 15% of the injected dose within 1 to 2 minutes. This rapid removal of {sup 125}I-APC from the circulation was found to be a result of an association with the liver regardless of the route of injection. Essentially identical results were obtained with active site-blocked forms of APC generated with either diisopropylfluorophosphate or D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone, which indicates that the active site was not essential for the liver association. Accumulation of all three forms of APC in the liver peaked at 30 minutes and then declined as increasing amounts of degraded radiolabeled material appeared in the gastrointestinal tract and urine. Removal of the gamma-carboxyglutamic acid (gla) domain of diisopropylphosphoryl-APC resulted in a 50% reduction in the association with liver and an accumulation in the kidneys. Protein C and protein S were cleared from themore » circulation at rates approximately one-half and one-fourth, respectively, that of APC. Both in vitro and in vivo, APC was found to form complexes with protease inhibitors present in guinea pig plasma. Complex formation resulted in a more rapid disappearance of the enzymatic activity of APC than elimination of the protein moiety. These findings indicate two distinct mechanisms for the elimination of APC. One mechanism involves reaction with plasma protease inhibitors and subsequent elimination by specific hepatic receptors. (Abstract Truncated)« less

Authors:
; ;  [1]
  1. (Wellcome Research Laboratories, Research Triangle Park, NC (USA))
Publication Date:
OSTI Identifier:
5761053
Resource Type:
Journal Article
Resource Relation:
Journal Name: Blood (Journal of Hematology); (USA); Journal Volume: 77:10
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; PROTEINS; BIOCHEMICAL REACTION KINETICS; THROMBOSIS; CHEMOTHERAPY; ANTICOAGULANTS; AUTORADIOGRAPHY; ELECTROPHORESIS; ENZYME ACTIVITY; ENZYME INHIBITORS; FIBRINOLYTIC AGENTS; GUINEA PIGS; IODINE 125; LIVER; METABOLISM; TISSUE DISTRIBUTION; ANIMALS; BETA DECAY RADIOISOTOPES; BODY; CARDIOVASCULAR DISEASES; DAYS LIVING RADIOISOTOPES; DIGESTIVE SYSTEM; DISEASES; DISTRIBUTION; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; GLANDS; HEMATOLOGIC AGENTS; INTERMEDIATE MASS NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IODINE ISOTOPES; ISOTOPES; KINETICS; MAMMALS; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANS; RADIOISOTOPES; REACTION KINETICS; RODENTS; THERAPY; VASCULAR DISEASES; VERTEBRATES; 550201* - Biochemistry- Tracer Techniques; 550901 - Pathology- Tracer Techniques

Citation Formats

Berger, H. Jr., Kirstein, C.G., and Orthner, C.L.. Pharmacokinetics of activated protein C in guinea pigs. United States: N. p., 1991. Web.
Berger, H. Jr., Kirstein, C.G., & Orthner, C.L.. Pharmacokinetics of activated protein C in guinea pigs. United States.
Berger, H. Jr., Kirstein, C.G., and Orthner, C.L.. 1991. "Pharmacokinetics of activated protein C in guinea pigs". United States. doi:.
@article{osti_5761053,
title = {Pharmacokinetics of activated protein C in guinea pigs},
author = {Berger, H. Jr. and Kirstein, C.G. and Orthner, C.L.},
abstractNote = {Protein C is a vitamin K-dependent zymogen of the serine protease, activated protein C (APC), an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent, the pharmacokinetics and tissue distribution of APC were studied in guinea pigs. The plasma elimination of a trace dose of {sup 125}I-APC was biphasic following an initial rapid elimination of approximately 15% of the injected dose within 1 to 2 minutes. This rapid removal of {sup 125}I-APC from the circulation was found to be a result of an association with the liver regardless of the route of injection. Essentially identical results were obtained with active site-blocked forms of APC generated with either diisopropylfluorophosphate or D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone, which indicates that the active site was not essential for the liver association. Accumulation of all three forms of APC in the liver peaked at 30 minutes and then declined as increasing amounts of degraded radiolabeled material appeared in the gastrointestinal tract and urine. Removal of the gamma-carboxyglutamic acid (gla) domain of diisopropylphosphoryl-APC resulted in a 50% reduction in the association with liver and an accumulation in the kidneys. Protein C and protein S were cleared from the circulation at rates approximately one-half and one-fourth, respectively, that of APC. Both in vitro and in vivo, APC was found to form complexes with protease inhibitors present in guinea pig plasma. Complex formation resulted in a more rapid disappearance of the enzymatic activity of APC than elimination of the protein moiety. These findings indicate two distinct mechanisms for the elimination of APC. One mechanism involves reaction with plasma protease inhibitors and subsequent elimination by specific hepatic receptors. (Abstract Truncated)},
doi = {},
journal = {Blood (Journal of Hematology); (USA)},
number = ,
volume = 77:10,
place = {United States},
year = 1991,
month = 5
}
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