Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Abstract

The circulatory persistence, distribution, and metabolism of hemoglobin-based oxygen carriers (HBOCs) is a major determinant of their safety and efficacy. In this communication, published data on the pharmacokinetics and routes of plasma elimination of HBOCs are summarized and evaluated. The circulating half-life of HBOCs is dose-dependent in both animals and humans. Half-life also increases with molecular weight in animals, at least up to the MDa range. The functional half-life of HBOCs is diminished by as much as 40% due to oxidation of the heme group relative to the overall rate of removal of hemoglobin (Hb) from plasma. Kidney excretion of HBOCs is greatly diminished compared to that of unmodified Hb, but the liver remains a primary site of catabolism. Both hepatocytes and Kupffer cells have been implicated in receptor-mediated HBOC uptake. Removal also occurs in the spleen and/or bone marrow and probably at dispersed sites in the endothelium as well. HBOCs extravasate into the lymph at a rate inversely proportional to their molecular weight and are taken up by monocyte/macrophage CD163 receptors, both as free Hb and in complexes with haptoglobin (Hp). The interactions with both Hp and the CD163 receptor are altered by Hb modification. However, monocyte/macrophage uptake may not be a quantitatively important route for the removal of clinically relevant doses of HBOCs. The relative contributions of different removal pathways have yet to be comprehensively determined, particularly in humans.

Keywords::

• crosslinked hemoglobins
• dose effects
• kidney excretion
• liver uptake
• metHb
• plasma half-life
• polymerized hemoglobins

Declaration of interest

Timothy Estep is a consultant for Omniox, Inc., an early stage biopharmaceutical company developing new medicines for hypoxic diseases. No financial, editorial, or writing support was received from Omniox for the production of this manuscript.