Colchicine-specific Fab fragments alter colchicine disposition in rabbits

High-affinity goat antibodies and Fab fragments (Ka = 1.1 x 10(10) M(-1) specific to colchicine were prepared to study their effect on colchicine pharmacokinetics in rabbits. First, colchicine disposition kinetics were investigated in four control rabbits after administration of 0.1 mg/kg i.v. Total and free plasma and urine colchicine were assayed by specific radioimmunoassay. The mean elimination half-life of total plasma colchicine was 16 +/- 2.9 h. Colchicine has a large volume of distribution (8.8 +/- 1.8 l/kg) and a low systemic clearance (114.6 +/- 3.4 ml.h-1.kg-1). Renal clearance represented 30.7 +/- 1.9% of total body clearance. The free plasma colchicine fraction was 70% after equilibrium dialysis. Second, 1.5 h after injection of 0.1 mg/kg colchicine, four rabbits were infused over 0.25 h with colchicine-specific Fab fragments at a half-stoichiometrically equivalent dose compared to the colchicine dose. Within 15 min after Fab infusion, total colchicine concentrations increased 10- to 16-fold. Mean area under the plasma concentration-time curves increased 20-fold compared to controls. The free plasma fraction decreased to an undetectable level over a period of 2 h. The Fab fragment administration also produced, respectively, a 24- and 17-fold decrease in the volume of distribution and systemic clearance. Colchicine recovered in urine was significantly higher than in the control group: 44.7 +/- 2.3 and 30.9 +/- 2% of the dose, respectively (P less than .05). These data suggest that high-affinity colchicine-specific Fab fragments can sequestrate and extract colchicine from tissues to the vascular compartment with subsequent colchicine excretion by the renal route.