Effect of von Willebrand factor on the pharmacokinetics of recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins.
Pharm Res
; 23(8): 1743-9, 2006 Aug.
Article
de En
| MEDLINE
| ID: mdl-16850270
ABSTRACT
PURPOSE:
Recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins (GPIbalpha-Ig) have varying levels of anti-thrombotic activities based on their ability to compete for platelet mediated adhesion to von Willebrand Factor (vWF). Valine substituted GPIbalpha-Ig chimeras, at certain position, increase the binding affinity to vWF over its "wild-type" GPIbalpha-Ig analog. The purpose of this study was to determine the pharmacokinetics of two valine substituted GPIbalpha-Ig chimeras, GPIbalpha-Ig/1V (valine substitution at 239 position) and GPIbalpha-Ig/2V (double valine substitution at 233 and 239 position), in mice, rats and dogs.METHODS:
Head-to-head comparisons of pharmacokinetics of GPIbalpha-Ig/1V and GPIbalpha-Ig/2V were investigated in rats and dogs after intravenous administration. Since vWF precipitates in the serum but not in plasma preparation, the concentration-time profiles of GPIbalpha-Ig/2V in rats were examined from the same blood samples for determination of matrix effect. The disposition of GPIbalpha-Ig/2V was also compared in vWF-deficient versus wild-type mice.RESULTS:
For GPIbalpha-Ig/2V, the serum clearances were 2.62+/-0.27 ml/hr/kg in rats and 1.97+/-0.24 ml/hr/kg in dogs. The serum clearances of less potent GPIbalpha-Ig/1V were 1.08+/-0.08 and 0.97+/-0.19 ml/hr/kg in rats and dogs, respectively. In addition, the serum clearance of GPlbalpha-Ig/2V of 1.53 ml/hr/kg in vWF-deficient mice was lower than that in wild-type mice of 2.79 ml/hr/kg.CONCLUSION:
The difference in disposition for valine substituted forms of GPIbalpha-Ig in laboratory animals are likely affected by their enhanced binding affinity for circulating vWF.
Recherche sur Google
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Facteur de von Willebrand
/
Complexe glycoprotéique GPIb-IX plaquettaire
Limites:
Animals
/
Female
/
Humans
/
Male
Langue:
En
Journal:
Pharm Res
Année:
2006
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique