Effect of colchicine-specific Fab fragments on the hepatic clearance of colchicine.
The influence of colchicine-specific Fab fragments on hepatic metabolism and biliary excretion of colchicine was studied in the isolated perfused rat liver. Isolated rat livers were perfused for 180 min with either [3H]colchicine (initial concentration: 50 ng/ml) or Fab-[3H] colchicine in a stoichiometrical proportion at a constant flow of 100 ml/min in a recirculating system. Based on perfusate concentrations, the hepatic extraction ratio of colchicine was more than 15-fold decreased when colchicine was bound to Fab fragments (E = 0.011 +/- 0.001) than when it was infused alone (E = 0.16 +/- 0.01) (p < 0.01). The extensive binding of colchicine to Fab over the experimental period as demonstrated by equilibrium dialysis (97 +/- 2%) prevented hepatic uptake. At the end of the colchicine perfusion experiment, 74.2 +/- 4.9% of the radioactivity infused was excreted by the biliary route. In contrast, biliary excretion of radioactivity was 10-fold lower when [3H]colchicine was perfused complexed with Fab fragments (p < 0.01). However, the metabolic profile of colchicine was not affected by Fab fragments. The apparent half-life of colchicine metabolites calculated from biliary data was similar to that of colchicine, indicating that the biliary excretion of these metabolites was formation rate-limited. Inhibition of colchicine uptake by specific Fab fragment was confirmed in vitro with isolated hepatocytes.
Sabouraud
A
A
INSERM U26, Paris, France.
Redureau
M
M
Gires
P
P
Martinet
M
M
Scherrmann
J M
JM
D000818:Animals; D000918:Antibody Specificity; D001646:Bile / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003078:Colchicine / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D007140:Immunoglobulin Fab Fragments; D014316:Tritium; D003078:Colchicine