The impact of polyethylene glycol conjugation on bovine hemoglobin's circulatory half-life and renal effects in a rabbit top-loaded transfusion model.
This study compares the effects of polyethylene glycol (PEG) modified bovine hemoglobin on vascular half-life and renal function in rabbits to those of unmodified bovine hemoglobin. Renal function was assessed by the measurement of the glomerular filtration rate, urinalysis, blood chemistries, hemoglobin (Hb) excretion rates, and tissue histology. The influence of infusion rates on hemoglobin excretion rates and organ morphology was also examined. The mean half-life of unmodified bovine hemoglobin was 3.0 +/- 0.1 (mean +/- SEM) h, which was extended 14-fold to 43.2 +/- 1.7 h following PEG conjugation. The glomerular filtration rate, urinalysis, and blood chemistries were not greatly affected by either the unmodified bovine hemoglobin or the PEG modified bovine hemoglobin. However, unmodified bovine hemoglobin did demonstrate significant hemoglobinuria (Hb excretion levels in excess of 1.0% of the infused dose [p < 0.05]) at all infusion rates given while PEG modified bovine hemoglobin did not. In addition, histological examination by light microscopy indicated that the most severe morphological changes occurred in animals that received unmodified bovine hemoglobin. This data suggests that PEG modification of bovine hemoglobin significantly reduced some of the adverse effects of bovine hemoglobin on renal physiology and morphology.
Conover
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CD
Research and Development, Formulations-Toxicology Department, Enzon Inc., Piscataway, New Jersey 08854, USA.
Gilbert
C W
CW
Shum
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KL
Shorr
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RG
D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001774:Blood Chemical Analysis; D001802:Blood Substitutes / Q000009:adverse effects / Q000737:chemistry; D001803:Blood Transfusion / Q000592:standards; D002417:Cattle; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006207:Half-Life; D006454:Hemoglobins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006456:Hemoglobinuria / Q000209:etiology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D012997:Solvents / Q000737:chemistry* / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016482:Urinalysis
D001802:Blood Substitutes; D006454:Hemoglobins; C109960:PEG-hemoglobin; D012997:Solvents; D011092:Polyethylene Glycols