DRUG-INTERACTION BETWEEN SIMVASTATIN AND CHOLESTYRAMINE IN-VITRO AND IN-VIVO

The interaction between simvastatin (SV), a prodrug lactone, HMG-CoA r eductase inhibitor which converts to the active hydroxy acid form (SVH ) in vivo, and cholestyramine (CT), an anionic exchange resin, was eva luated both in vitro and in vivo. In an in vitro SV-stability study, i t was shown that SV degraded gradually to SVH in an aqueous solution a t pH 2 and 7. To evaluate the binding ability of SV or SVH to er, the incubation of 5 mu g/ml of SV or SVH solution with 200 mg of CT in var ious 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 interac tion 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. SV H 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 t he following procedure: SV underwent hydrolysis to SVH in aqueous solu tion, then CT activated the hydrolysis by binding the formed SVH, resu lting in a significant reduction in concentration of SV. On the other hand, an in vivo animal experiment also demonstrated a significant red uction (about 50% with AUG) in the concentration of SVH in plasma foll owing 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 sug gested that a combination therapy using SV and CT might result in a sm aller cholesterol-lowering effect of SV.