Pharmacokinetics of activated protein C in guinea pigs
H Berger , CG Kirstein and CL Orthner
Division of Pharmacology, Wellcome Research Laboratories, Research Traingle
Park, NC 27709.
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 125I-APC was
biphasic following an initial rapid elimination of approximately 15% of the
injected dose within 1 to 2 minutes. This rapid removal of 125I-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. The other mechanism involves the
direct catabolism of APC by the liver via a pathway that is nonsaturable
over a substantial dose range and independent of the active site. This
pattern of elimination is distinctly different from that observed with the
homologous coagulation enzymes thrombin, factor IXa, and factor Xa.
Volume 77,
Issue 10,
pp. 2174-2184,
05/15/1991
Copyright © 1991 by The American Society of Hematology
