Pharmacokinetics of argatroban in primates: Evidence on endogenous uptake

Background. Antithrombin agent, argatroban, is currently undergoing several clinical trials for cardiovascular indications. Because of its solubility, this drug is usually administered ria an intravenous bolus followed by inf usion. The purpose of this study was to determine the pharmacokinetics of a rgatroban after intravenous bolus injection in primates. Methods. Parallel in vitro studies in primate whole blood were carried out to simulate a one-compartment system. Argatroban (range 1.0-7.5 mg/kg) was administered to four groups of primates and blood samples were drawn at var ious time periods. Argatroban measurements were made in plasma using functi onal (aPTT, Heptest, TT) and HPLC methods. Results. In vitro, argatroban primarily distributed in the plasma in propor tionate amounts. Relative uptake of argatroban to the blood cells (leukocyt es and erythrocytes) was minimum. However, in vitro, argatroban followed a complex pharmacokinetics, Within 5 min after the bolus administration, only <20% of argatroban was recovered. The recovered amount tvas proportionate to the dosage and followed the expected kinetics with a half-life of <20 mi n. Simultaneous quantitation of M1-metabolite of argatroban revealed only a fraction of recovered argatroban (similar to 25%) converted into M1 in the se experimental settings. Results obtained from the functional and absolute methods correlated well. HPLC profile did not reveal the presence of any o ther metabolite(s), Conclusions. These observations suggest that argatroban mag be endogenously taken up by the vascular or other sites and may exhibit a complex kinetics . In acute settings, the metabolic transformation of argatroban to M1 is re latively low. To further clarify the pharmacokinetics/pharmacodynamics of t his drug, additional studies are warranted.