Zero-order absorption and linear disposition of oral colchicine in healthy volunteers

Summary

The pharmacokinetics of colchicine has been studied in nine healthy male volunteers after oral doses of 0.5, 1, and 1.5 mg as tablets. Plasma and urine samples were collected over 48 h and analysed for colchicine by radioimmunoassay.

Individual colchicine concentration profiles in plasma and urine were well described by a two-compartment open model with zero-order input. Considering the absorption variables as specific to each experiment, the lag time (0–0.35 h) and duration (0.39–2.38 h) of absorption were found to be independent of dose, while the zero-order rate constant of absorption (k₀) increased linearly with dose.

Disposition variables were taken as common to the three experiments, except in six subjects in whom renal excretion varied significantly across experiments in a dose-independent manner. For seven subjects the terminal half-life was 19.4 h, the oral apparent volume of distribution at steady-state (V_ss/f) was 691 l, and the oral systemic clearance (CL/f) was 33.1 l·h⁻¹. In the two other subjects, the values were unreliable, but the estimated terminal half-life was greater than 48 h, V_ss/f ranged from 1690 to 3480 l, and CL/f was in the range of the other subjects in 1 subject, and it was about 15l·h⁻¹ in the other. In the latter subject, these estimates, together with the observation that plasma concentration reached a plateau at 2 to 5 h after ingestion, suggest enterohepatic cycling of colchicine.

Overall, the disposition of colchicine was linear in the dose range 0.5–1.5 mg, with a long terminal half-life, and absorption obeyed zero-order kinetics, with k₀ proportional to dose.