Abstract
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 (
V
c
,
V
ss
and
V
area
). 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 (K
21) and out of the central compartment (
K
10). 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.