The mechanism associated with the increased bioavailability of tacrine as a result of a 24-h period of fasting was examined in rats. The AUC value for tacrine after the fasting was 52% higher compared with normal feeding when 4 mg kg-1 of tacrine was orally administered, but the value for velnacrine, a hydroxylated metabolite of tacrine, was reduced by 10%. The relative metabolic ratio of tacrine in urinary excretion (Autacrine divided by Auvelnacrine) was lower in fasted rats compared with normally fed rats. This clearly shows that metabolism of tacrine is reduced with 24-h fasting after oral administration. Altered intestinal permeation in the fasting state was hypothesized, and the transport of tacrine across the rat intestine was studied. When a fasted intestine was mounted in an Ussing chamber, the mucosalto-serosal permeability of tacrine was increased to double that for a fed rat intestine. To examine the effect of absorption rate on the hepatic metabolism of tacrine, a direct pyloric vein infusion study was carried out. Compared with an infusion of tacrine for 5 min, a slow infusion of tacrine over a period of 30 or 60 min increased the hepatic metabolism of tacrine and decreased its systemic clearance in rats. Collectively, these results suggest that rapid transport across the intestine aids tacrine in avoiding hepatic first-pass metabolism and enhances its bioavailability in fasted rats. From these findings, we conclude that both oral administration before a meal and a reduction in the dose might be recommended in tacrine therapy considering the serious hepatotoxicity of tacrine in clinical use.