Summary
Pharmacokinetics of oligosaccharides displaying various affinities for antithrombin
(AT) allowed us to show that there was a close relationship between the plasma half-life
of these antithrombotic oligosaccharides and their affinity for AT. Recently, we have
described new heparin mimetics comprising an AT binding domain and a thrombin binding
domain separated by a neutral methylated saccharide sequence. These compounds displayed
strong anti-Xa and anti-IIA activities and, in contrast to heparin, escaped neutralisation
by platelet factor 4. The aim of this work was to compare the pharmacokinetics of
several of these heparin mimetics in rats. These compounds differed by their length,
charge and affinity for AT (AT-binding domain). The results obtained indicate that
the prolongation of the AT binding domain did not modify significantly their affinities
for AT. However, an increase in the number of charges leads to a decrease in the half-life.
When a methylated spacer was added in order to minimise the non-specific interactions
to other proteins, half-lives of the heparin mimetic were in the same range than that
of the pentasaccharide used as an AT binding domain.
In conclusion, this study shows the influence of the charge of the oligosaccharides
on their pharmacokinetics and underlines the importance of minimising their non-specific
binding to plasma proteins in order to obtain compounds with predictive pharmacokinetics.
Keywords
Antithrombin - heparin - pentasaccharide
