Modeling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species-pharmacokinetic and therapeutic implications.
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Boretti FS
Division of Veterinary Internal Medicine, School of Veterinary Medicine, University of Zurich Zurich, Switzerland.
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Baek JH
Laboratory of Biochemistry and Vascular Biology, FDA Center for Biologics Evaluation and Research Bethesda, MD, USA.
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Palmer AF
Chemical and Biomolecular Engineering, The Ohio State University Columbus, OH, USA.
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Schaer DJ
Division of Internal Medicine, University of Zurich Hospital, University of Zurich Zurich, Switzerland.
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Buehler PW
Laboratory of Biochemistry and Vascular Biology, FDA Center for Biologics Evaluation and Research Bethesda, MD, USA.
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Published in:
- Frontiers in physiology. - 2014
English
BACKGROUND
Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes.
OBJECTIVE
The focus of this study is to understand Hb:Hp clearance in a non-rodent species. In contrast to rodents, dogs maintain high plasma Hp concentrations comparable to humans and demonstrate more rapid clearance of Hb:Hp when compared to rodent species, therefore dogs may represent a relevant species to evaluate Hb:Hp pharmacokinetics and cellular clearance.
RESULTS
In this study we show, that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp complexes. The data demonstrate a significantly reduced volume of distribution (Vc) for Hb:Hp compared to free Hb, increased maximum plasma concentrations and areas under plasma concentration time curves (Cmax and AUC). Significantly reduced total body clearance (CL) and a longer terminal half-life (t1/2) of approximately 12 h were also observed for the Hb:Hp complex. Distribution and clearance were identical for dimeric and multimeric Hb:Hp complexes. We found no significant effect of a high-dose glucocorticoid treatment protocol on Hb:Hp pharmacokinetic parameter estimates.
CONCLUSION
Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp as a therapeutic in diseases of hemolysis.
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gold
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https://sonar.ch/global/documents/47836
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