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| Content Provider | Springer Nature Link |
|---|---|
| Author | Wang, Qin Shorten, Douglas Xu, Xin Shaw, Gray D. Schaub, Robert G. Shea, Christopher Brooks, Jonathan Sako, Dianne Wiswall, Erin Xu, Jin Szklut, Pamela Patel, Vikram S. |
| Copyright Year | 2006 |
| Abstract | Recombinant human platelet glycoprotein Ibα-immunoglobulin G1 chimeric proteins (GPIbα-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 GPIbα-Ig chimeras, at certain position, increase the binding affinity to vWF over its “wild-type” GPIbα-Ig analog. The purpose of this study was to determine the pharmacokinetics of two valine substituted GPIbα-Ig chimeras, GPIbα-Ig/1V (valine substitution at 239 position) and GPIbα-Ig/2V (double valine substitution at 233 and 239 position), in mice, rats and dogs.Head-to-head comparisons of pharmacokinetics of GPIbα-Ig/1V and GPIbα-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 GPIbα-Ig/2V in rats were examined from the same blood samples for determination of matrix effect. The disposition of GPIbα-Ig/2V was also compared in vWF-deficient versus wild-type mice.For GPIbα-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 GPIbα-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 GPIbα-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.The difference in disposition for valine substituted forms of GPIbα-Ig in laboratory animals are likely affected by their enhanced binding affinity for circulating vWF. |
| Starting Page | 1743 |
| Ending Page | 1749 |
| Page Count | 7 |
| File Format | |
| ISSN | 07248741 |
| Journal | Pharmaceutical Research |
| Volume Number | 23 |
| Issue Number | 8 |
| e-ISSN | 1573904X |
| Language | English |
| Publisher | Kluwer Academic Publishers-Plenum Publishers |
| Publisher Date | 2006-07-19 |
| Publisher Place | New York |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | factor VIII GPIbα_Ig pharmacokinetics of recombinant protein vWF vWF antibody Biomedical Engineering Medical Law Biochemistry Pharmacy Pharmacology/Toxicology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science |
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