ABSTRACT
A model of functional nephrectomy and hepatectomy in rats was used to compare the
pharmacokinetic profile of the direct competitive thrombin inhibitor argatroban in
rats with renal, hepatic, or hepatorenal failure and rats with normal hepatic and
renal function. The pharmacokinetics of argatroban in rats after an intravenous bolus
was described by an open two-compartment model with first-order elimination. This
profile was not affected in nephrectomized rats, but hepatectomized rats showed a
markedly increase in area under the curve values, distribution, and elimination half-life
in comparison with untreated rats as expected for a drug eliminated primarily by the
liver. Unexpectedly, blood levels of argatroban were lower in rats with hepatorenal
failure than in rats with only hepatic failure. Similar results were observed after
subcutaneous administration of argatroban. We propose that argatroban might be converted
from 21–(R) to 21-(S) diastereoisomer in the kidneys. The 21-(S) diastereoisomer has
a higher antithrombotic activity than the R isoform and this 21-(S) isomer might be
preferentially hepatically eliminated. This could explain the higher anticoagulant
activity in blood of hepatectomized rats with normal renal function in comparison
with rats with hepatorenal failure.
KEYWORDS
Argatroban - pharmacokinetics - renal failure - hepatic failure - hepatorenal failure
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Prof. Dr. Götz NowakM.D.
University Medical Center Jena, Research Group “Pharmacological Haemostaseology,”
Drackendorfer Str. 1
07747 Jena, Germany
Email: AGPHH@med.uni-jena.de
