Tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA), Cognex] is a potent acetylcholinesterase inhibitor recently approved for treatment of mild-to-moderate Alzheimer's disease. The potential for THA and/or a metabolite of THA to accumulate in brain tissue was investigated by autoradiographic and metabolic profiling techniques in rats given single and multiple doses of [14C]THA. In addition, the brain-to-plasma distribution time course of orally administered 1-hydroxy-THA (1-OH-THA, 24 mg/kg), a primary rat metabolite with anticholinesterase activity, was also examined. Results from a 16 mg/kg single-dose study showed THA to cross the blood-brain barrier readily and concentrate in brain tissue, approximately 5-fold compared with plasma. The metabolite 1-OH-THA was found in much lower amounts relative to THA and when given separately at a similar dose the levels in brain tissue were comparable with plasma concentrations. After multiple-dose administration, THA concentrations in brain tissue were approximately 3-fold higher than those achieved after a single oral dose. However, concentration of 1-OH-THA metabolite increased only 50%. These data suggest a marked difference between the ability of THA and 1-OH-THA to accumulate in brain tissue and may reflect differences in lipophilicity as estimated by calculated log p values. The relevance of THA accumulation in brain tissue to delays observed in THA clinical management of Alzheimer's disease remains to be established.