INTERRUPTION OF THE ENTEROHEPATIC CIRCULATION OF INDOMETHACIN BY CHOLESTYRAMINE IN RABBITS

The purpose of this investigation was to determine whether the oral administration of cholestyramine would increase the systemic clearance of indomethacin following intravenous administration (2 mg/kg) to rabbits. In cholestyramine-treated rabbits a significant reduction in indomethacin serum concentration was observed compared to control animals. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half-life (1.26 ± 0.13 and 0.85 ± 0.06 h for the control and treated groups, respectively) and the mean residence time (1.31 ± 0.13 and 0.78 ± 0.04 h for the control and treated rabbits, respectively). Furthermore, a 56% increase in the systemic clearance (1.91 ± 0.17 and 2.99 ± 0.2 ml min-1 kg-1 for the control and treated rabbits, respectively) and 36% decrease in the area under the serum concentration-time curve (17.57 ± 1.62 and 11.19 ± 0.7 μg h ml(su for the control and treated rabbits, respectively) were also observed. Cholestyramine administration did not significantly alter the apparent volume of distribution parameters (Vc,Vss and Varea). Regarding the microconstants of the two-compartment model which adequately described indomethacin kinetic in control and treated rabbits, cholestyramine administration produced a significant increase in the rate of transfer of indomethacin from the tissue compartment (K21) and out of the central compartment (K10). These findings indicate that cholestyramine administration accelerates the systemic elimination of indomethacin. This effect is thought to be due to augmentation of net biliary excretion through enteric binding. © 1990.