Influence of goat colchicine specific antibodies on murine colchicine disposition

The potential use of colchicine-specific antibodies (IgG(C)) to overcome colchicine intoxication in mice is of interest in human poisoning. Pharmacokinetics in mice are similar to those in humans. A short distribution half-life (t 1/2 a = 34 min) is associated with a long elimination half-life (t1/2 beta = 48 h) together with a large volume of distribution at steady-state (Vss = 2.5 l/kg) and a low total body clearance (ClT = 1 ml/min/kg). This extensive and rapid distribution to tissues impairs the success of conventional therapies. Despite the administration of a relatively low amount of IgG (C) (15% binding sites vs, colchicine molecules), the beneficial effect of IgG(C) is demonstrated by the alteration in colchicine pharmacokinetics which occurs rapidly following IgG(C) administration as demonstrated by rise in blood toxin concentrations (4-fold relative to IgG(N)-treated controls). This sequestration in the blood is associated with a colchicine redistribution from peripheral to the blood compartment. This extraction effect is revealed by lower colchicine tissue levels in IgG(C)-treated mice than in controls. As a consequence, Vss decreased in the IgG(C) group. Moreover, ClT is diminished in the IgG(C)-treated group because the relatively large immunoglobulin can not be excreted renally. In addition to this toxin displacement, study of free and bound colchicine plasma levels shows a lower percentage of free toxin in the IgG(C)-treated group (33 to 0%) compared to 70% in the control group. This pharmacokinetic study provides evidence that the administration of IgG(C) alters the colchicine disposition by sequestrating and extracting colchicine in blood compartment.