Pharmacokinetics of activated protein C in guinea pigs
- Wellcome Research Laboratories, Research Triangle Park, NC (USA)
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)
- OSTI ID:
- 5761053
- Journal Information:
- Blood (Journal of Hematology); (USA), Vol. 77:10; ISSN 0006-4971
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
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