Pharmacokinetics and organ distribution of cationized colchicine-specific IgG and Fab fragments in rat.
Pharmacokinetics of cationized goat colchicine-specific polyclonal immunoglobulin G (IgG) and antigen binding fragment (Fab) (cIgG and cFab, respectively) were studied in male adult Sprague-Dawley rats and compared with those of the native proteins (nIgG and nFab). All proteins were radioiodinated by the Iodogen method, and kinetics were investigated following trichloroacetic acid (TCA) precipitation or immunoprecipitation. Deiodination and catabolism were more pronounced with the cationized than the native proteins, especially for cFab. Both cIgG and cFab in plasma decreased more rapidly than nIgG and nFab. The elimination half-lives were 52.9 and 81.8 h for cIgG and nIgG, respectively. In addition, there was a 74-fold increase in the volume of distribution and a 114-fold increase in the systemic clearance of cIgG compared with nIgG. For cFab, the volume of distribution and systemic clearance were increased 6.4- and 3.5-fold, respectively. Organ uptake of cIgG and cFab was markedly increased compared with that of nIgG and nFab, especially in kidney, liver, spleen, and lung. Renal clearance of cIgG and cFab was also increased 30- and 10-fold compared with that of nIgG and nFab, respectively. The present data suggest that cationization of colchicine-specific IgG and Fab fragments increased the organ distribution and greatly altered their pharmacokinetics. Nevertheless, the smaller molecular size of Fab versus IgG did not enhance the distribution and clearance of cFab. These data pave the way for evaluating the biological efficacy of these more tissue-organ-interactive antibodies.
Hong
G
G
Inserm U26 and Department of Pharmacokinetics, University of Paris V, Hôpital Fernand Widal, Paris, France.
Bazin-Redureau
M I
MI
Scherrmann
J M
JM
D000818:Animals; D000906:Antibodies / Q000032:analysis; D001345:Autoradiography; D003078:Colchicine / Q000737:chemistry / Q000493:pharmacokinetics*; D003599:Cytoskeleton / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D006041:Goats / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D007074:Immunoglobulin G / Q000737:chemistry*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008297:Male; D010865:Pilot Projects; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014404:Tubulin / Q000187:drug effects
D000906:Antibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D014404:Tubulin; D003078:Colchicine