The effect of liver dysfunction on colchicine pharmacokinetics in the rat

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P‐450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham‐operated controls), α‐naphthylisothiocyanate‐induced intrahepatic cholestasis and galactosamine‐induced diffuse hepatocelluar necrosis. The control group had a colchicine clearance of 77.33 ml/min. kg ± 8.27 ml/min kg, a half‐life of 16.68 min ± 0.97 min and a volume of distribution of 1.84 L/kg ± 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p < 0.05) and half‐life to increase by 38% (p < 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p < 0.05), terminal half‐life increased to 513.7 min ± 106.6 min (p < 0.05) and volume of distribution increased by 175% (p < 0.05). Colchicine pharmacokinetics in sham‐operated rats were not statistically different from the above mentioned controls. After α‐naphthylisothiocyanate administration, colchicine clearance decreased by 55% (p < 0.05), the halflife increased by 56% (p < 0.05) and the volume of distribution decreased by 30% (p < 0.05). After administration of galactosamine, 1,000 mg/kg, colchicine clearance decreased by 62% (p < 0.05), half‐life increased to 144.72 min ± 35.30 min (p < 0.05) and volume of distribution increased by 124% (p < 0.05). These data show that experimental hepatic injury in the rat significantly impairs colchicine pharmacokinetics. They also support the hypothesis that the liver is a major route of colchicine elimination.