The interaction between simvastatin (SV), a prodrug lactone, HMG-CoA reductase inhibitor which converts to the active hydroxy acid form (SVH) in vivo, and cholestyramine (CT), an anionic exchange resin, was evaluated both in vitro and in vivo. In an in vitro SV-stability study, it was shown that SV degraded gradually to SVH in an aqueous solution at pH 2 and 7. To evaluate the binding ability of SV or SVH to CT, the incubation of 5 micrograms/ml of SV or SVH solution with 200 mg of CT in various pH (2.0, 5.0 and 7.0) solutions was performed at 37 degrees C for 10 min. After incubation, the concentration of SV decreased by 59.02% (pH 2), 63.90% (pH 5) and 67.36% (pH 7), respectively, and an interaction between SV and CT was suggested. The values were much larger than those expected from the stability test of SV in the absence of CT. SVH was found to bind more strongly to CT. The binding ability of SVH to CT was 66.71% (pH 2), 87.44% (pH 5) and 92.11% (pH 7), respectively. Judging from these results, SV was considered to interact with CT by the following procedure: SV underwent hydrolysis to SVH in aqueous solution, then CT activated the hydrolysis by binding the formed SVH, resulting in a significant reduction in concentration of SV. On the other hand, an in vivo animal experiment also demonstrated a significant reduction (about 50% with AUC) in the concentration of SVH in plasma following the coadministration of SV (500 mg/kg p.o.) and CT (600 mg/kg p.o.), compared with the administration of SV alone. This phenomenon suggested that a combination therapy using SV and CT might result in a smaller cholesterol-lowering effect of SV.