Abstract
Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species. Plasma AA decreased by 50% in guinea pigs after ET, but it was unchanged in rats for the first 20 h post-ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was 5-fold greater in the guinea pig. Mass spectrometry analysis of plasma revealed oxidative modifications within the tetrameric fraction of PolyHbBv in guinea pig. Oxygen equilibrium curves of PolyHbBv measured in plasma after ET were more left-shifted in guinea pigs compared with rats, consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF)-1α, whose activity strictly depends on the partial pressure of oxygen increased over time, and it correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1α activity was greater in guinea pigs compared with rats at 72 h post-ET. Mean arterial pressure increases were also greater in guinea pigs; however, minimal differences in cardiac and renal pathology were observed in either species. The present findings suggest the importance of plasma AA in maintaining the stability of acellular Hb susceptible to oxidation, and they may be relevant to humans, which display a similar plasma/tissue antioxidant status to guinea pig.
Footnotes
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The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration, and they should not be construed to represent any agency determination or policy. This work was funded by a Center for Biologics Evaluation and Research/Food and Drug Administration Unmet Needs Award.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126409.
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ABBREVIATIONS: HBOC, hemoglobin-based oxygen carrier; AA, ascorbic acid; LGO, l-gulonolactone oxidase; DHA, dehydroascorbate; PolyHbBv, bovine polymerized hemoglobin; PE, polyethylene; MAP, mean arterial pressure; ET, exchange transfusion; Hct, hematocrit; HIF, hypoxia-inducible factor; MALDI-MS, matrix-assisted laser desorption ionization/mass spectrometry; RBC, red blood cell; PK, pharmacokinetic; AUC, area under the plasma-concentration time curve; CL, plasma clearance; MRT, mean residence time; Vss, apparent volume of distribution at steady state; OEC, oxygen equilibrium curve; Clast, last measurable concentration; SEC, size exclusion chromatography; BL, baseline; PEG, polyethylene glycol.
- Received May 30, 2007.
- Accepted July 9, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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