The pharmacokinetics of the cholinesterase inhibitor tacrine was studied in 5 Alzheimer patients during 12-31 months of treatment. A mean average steady-state concentration in plasma ranging from 1.1 to 30 ng/ml was obtained with doses ranging from 40 to 160 mg of tacrine daily. During treatment with 80 mg daily a maximal plasma concentration of tacrine (8.7 +/- 0.6 ng/ml) was obtained 1.3 +/- 0.2 h after intake of the morning dose. The mean elimination half-life was estimated at 5-7 h and remained unchanged when the tacrine dose was increased. The plasma concentration of tacrine was stable during long-term treatment with tacrine and no tolerance was observed regarding its cholinesterase inhibitory effect. A maximal 40% inhibition of plasma cholinesterase (ChE) activity and 60% inhibition of acetylcholinesterase activity in red blood cells was measured following treatment with the highest dose of 160 mg tacrine daily. A significant correlation was obtained between the plasma concentration of tacrine and the inhibition of ChE activity (p < 0.001). The tacrine concentration in CSF was measured in each patient on 1-3 occasions during the treatment and the ratio CSF/plasma concentration was estimated to be 0.47 +/- 0.09 (n = 11).