Pharmacokinetics of extracellular-superoxide dismutase in the vascular system.
Extracellular-superoxide dismutase C (EC-SOD C) is a secretory tetrameric Cu- and Zn-containing glycoprotein which has high affinity for heparin and heparan sulfate. Upon intravenous injection into rabbits, recombinant human (rh) EC-SOD C was found to be rapidly 97-98% sequestered to the vascular wall, forming an equilibrium with the plasma phase. Recombinant EC-SOD truncation variants with reduced, T216, and without, T213, heparin affinity were found to be sequestered to a reduced extent and not at all, respectively, establishing the importance of the heparin affinity for this behaviour. The halflife of rhEC-SOD C in the vasculature was of the order of 20 h. Injection of large doses resulted in saturation of the binding of rhEC-SOD C to the vascular wall. Scatchard analysis revealed a heterogeneity in affinity of the ligands on the vascular wall. The maximal binding capacity was very high. The equilibration of rhEC-SOD C to the vascular wall of an organ, clamped during enzyme injection, and the primary equilibration phase was studied by comparing binding to a clamped and reperfused kidney with binding to the contralateral control kidney. rhEC-SOD C injected in a low dose was found to equilibrate very slowly to the reperfused kidney with a halftime of about 2 h. With higher rhEC-SOD C doses, at which evidence for saturation is seen, and with the variant rhEC-SOD with reduced heparin affinity. T216, very rapid equilibrations were found.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Clinical Chemistry, Umeå University Hospital, Sweden.
K
K
Karlsson
J
J
Sandström
A
A
Edlund
T
T
Edlund
S L
SL
Marklund
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D005260:Female; D005609:Free Radicals; D014644:Genetic Variation; D006493:Heparin / Q000378:metabolism; D007511:Ischemia; D007668:Kidney / Q000098:blood supply; D007700:Kinetics; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics; D015424:Reperfusion; D013482:Superoxide Dismutase / Q000378:metabolism / Q000493:pharmacokinetics*; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D011994:Recombinant Proteins; D013481:Superoxides; D006493:Heparin; D013482:Superoxide Dismutase