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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 10, 2007; DOI: 10.1124/jpet.107.126409

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*Compound via MeSH
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*ASCORBIC ACID
*OXYGEN
*SODIUM ASCORBATE


Received for publication May 30, 2007.
Revised July 9, 2007.
Accepted for publication July 9, 2007.

Effects of endogenous ascorbate on oxidation, oxygenation and toxicokinetics of cell-free modified hemoglobin after exchange transfusion in rat and guinea pig

Paul W. Buehler 1*, Felice D'Agnillo 2, Victoria Hoffman 3, Abdu I. Alayash 2

1 Food and Drug Administration/CBER 2 FDA 3 NIH

* Address correspondence to: E-mail: paul.buehler{at}fda.hhs.gov

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 guinea pigs, a non-AA producing species. Plasma AA decreased by 50% in guinea pigs after ET but was unchanged in rats for the first 20 hours post ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was five-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 (OECs) of PolyHbBv measured in plasma after ET were more left shifted in guinea pigs compared to rats consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF-1{alpha}), whose activity strictly depends on PO2 increased over time and correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1{alpha} activity was greater in guinea pigs compared to rats at 72 hours 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 therapeutic agents susceptible to oxidation and may be relevant to humans which display a similar plasma/tissue antioxidant status to guinea pig.


Key words: Non-compartmental pharmacokinetic, ascorbic acid, ferric hemoglobin, histopathology, plasma reductive capacity, toxicokinetics


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