title: The intravascular persistence and methemoglobin formation of Hemolink (hemoglobin raffimer) in dogs.
abstract: Hemoglobin raffimer (HEMOLINK, Hemosol Inc, Mississauga, Canada) is an o-raffinose cross-linked, purified human hemoglobin-based oxygen therapeutic that is currently being evaluated in late stage clinical trials. It is composed of several molecular weight (MW) species, comprising principally of stabilized tetramers (34-42%) and oligomers (54-62%). The objective of this study was to determine the in vivo circulating half-life (T1/2) of hemoglobin raffimer (Hb raffimer) and of its individual MW components in dogs subjected to a topload infusion of 25% of the estimated blood volume (18 mL/kg). Sampling was done over a 64-hour period that was expected to be equivalent to approximately two-and-half to three half-lives. Methemoglobin (MetHb) levels were also measured at intervals over the same period. The mean circulating half-life of Hb raffimer was 25.4 +/- 3.9 hours. The T1/2 for the individual MW components (determined by size exclusion chromatography) of Hb raffimer was 11 +/- 2 hours for the cross-linked tetramer and 35 +/- 7 hours for the fraction of oligomers. The apparent volume of distribution for Hb raffimer was estimated at 78 mL/kg. There was no difference in the apparent volumes of distribution of the tetrameric and oligomeric components of Hb raffimer. Throughout the course of the experiment (in which MetHb could be measured), plasma MetHb concentration, expressed as a percentage of the total plasma hemoglobin concentration, remained at 10% or less, and the mass concentration of MetHb in plasma remained at about 1 g/L. Thus, in the dog subjected to an estimated 25% topload infusion, the T1/2 of the infused Hb raffimer is approximately one day with the intravascular retention of the individual Hb raffimer components being dependent on the MW. Furthermore, oxidation of Hb raffimer to MetHb is limited under these conditions.
authors.affiliation: Hemosol Inc., Mississauga, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Wicks
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Wong
authors.forename: Reena
authors.initials: R
authors.lastname: Sandhu
authors.forename: Richard K
authors.initials: RK
authors.lastname: Stewart
authors.forename: George P
authors.initials: GP
authors.lastname: Biro
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D006207:Half-Life; D006454:Hemoglobins / Q000378:metabolism / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008706:Methemoglobin / Q000378:metabolism*; D008970:Molecular Weight; D010084:Oxidation-Reduction; D011887:Raffinose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; C097124:O-raffinose cross-linked human hemoglobin; D008706:Methemoglobin; D011887:Raffinose