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Rivista di Angiologia

Official Journal of the International Union of Angiology, the International Union of Phlebology and the Central European Vascular Forum
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International Angiology 2000 June;19(2):126-34


lingua: Inglese

Pharmacokinetics of argatroban in primates: Evidence on endogenous uptake

Ahmad S., Yang L. H., Ahsan A., Fu K., Iqbal O., Hoppensteadt D. A., Lewis B. E., Walenga J. M., Fareed J.

From the Departments of Pathology, Pharmacology, and Thoracic-Cardiovascular Surgery, Loyola, University Chicago Stritch School of Medicine, Maywood, Illinois, USA.


Background. The antithrombin agent, argat­ro­ban, is cur­rent­ly under­go­ing sev­er­al clin­i­cal ­trials for car­di­o­vas­cu­lar indi­ca­tions. Because of its sol­u­bil­ity, this drug is usu­al­ly admin­is­tered via an intra­ve­nous bolus fol­lowed by infu­sion. The pur­pose of this study was to deter­mine the phar­ma­cok­i­net­ics of argat­ro­ban 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 var­i­ous time peri­ods. Argatroban meas­ure­ments were made in plas­ma using func­tion­al (aPTT, Heptest, TT) and HPLC meth­ods.
Results. In vitro, argat­ro­ban pri­mar­i­ly dis­trib­ut­ed in the plas­ma in pro­por­tion­ate ­amounts. Relative ­uptake of argat­ro­ban to the blood cells (leu­ko­cytes and eryth­roc­y­tes) was min­i­mum. However, in vivo, argat­ro­ban fol­lowed a com­plex phar­ma­cok­i­net­ics. Within 5 min after the bolus admin­is­tra­tion, only <20% of argat­ro­ban was recov­ered. The recov­ered ­amount was pro­por­tion­ate to the dos­age and fol­lowed the expect­ed kinet­ics with a half-life of
<20 min. Simultaneous quan­ti­ta­tion of M1-metab­olite of argat­ro­ban ­revealed only a frac­tion of recov­ered argat­ro­ban (~25%) con­vert­ed into M1 in these experi­men­tal set­tings. Results ­obtained from the func­tion­al and abso­lute meth­ods cor­re­lat­ed well. HPLC pro­file did not ­reveal the pres­ence of any other metab­olite(s).
Conclusions. These obser­va­tions sug­gest that argat­ro­ban may 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 rel­a­tive­ly low. To fur­ther clar­i­fy the phar­ma­cok­i­net­ics/phar­ma­cod­y­nam­ics of this drug, addi­tion­al stud­ies are war­rant­ed.

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