HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Ship, N. J. Articles by Pang, K. S. Search for Related Content PubMed PubMed Citation Articles by Ship, N. J. Articles by Pang, K. S.

LIVER AND BILIARY TRACT

Binding of acellular, native and cross-linked human hemoglobins to haptoglobin: enhanced distribution and clearance in the rat

¹Davenport Laboratory, Department of Chemistry, and ²Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Submitted 1 September 2004 ; accepted in final form 2 December 2004

It is well established that hemoglobin resulting from red cell lysis binds to haptoglobin in plasma to form a complex. The increased molecular size precludes its filtration by the kidneys, redirecting it toward hepatocellular entry. Chemically cross-linked hemoglobins are designed to be resistant to renal excretion, even in the absence of haptoglobin. The manner in which binding to haptoglobin influences the pharmacokinetics of acellular cross-linked and native hemoglobins was investigated after intravenous injection of radiolabeled native human hemoglobin and trimesyl-(Lys82)-(Lys82) cross-linked human hemoglobin, at trace doses, into rats. Under these conditions, there is sufficient plasma haptoglobin for binding with hemoglobin. In vitro binding assayed by size-exclusion chromatography for bound and free hemoglobin revealed that, at <8 µM hemoglobin, native human hemoglobin was completely bound to rat haptoglobin, whereas only 30% of trimesyl-(Lys82)-(Lys82) cross-linked hemoglobin was bound. Plasma disappearance of low doses (0.31 µmol/kg) of native and cross-linked hemoglobins was monoexponential (half-life = 23 and 33 min, respectively). The volume of distribution (40 vs. 19 ml/kg) and plasma clearance (1.22 vs. 0.4 ml·min^–1·kg^–1) were higher for native than for cross-linked hemoglobin. Native and cross-linked human hemoglobins were found primarily in the liver, and not in the kidney, heart, lung, or spleen, mostly as degradation products. These pharmacokinetic findings suggest that the binding of hemoglobin to haptoglobin enhances its hepatocellular entry, clearance, and distribution.

organ disposition; liver transport; clearance

This article has been cited by other articles:

				E. C. Y. Chow, L. Liu, N. Ship, R. H. Kluger, and K. S. Pang Role of Haptoglobin on the Uptake of Native and {beta}-Chain [Trimesoyl-(Lys82){beta}-(Lys82){beta}] Cross-Linked Human Hemoglobins in Isolated Perfused Rat Livers Drug Metab. Dispos., May 1, 2008; 36(5): 937 - 945. [Abstract] [Full Text] [PDF]