DISTRIBUTION OF TACRINE AND METABOLITES IN RAT-BRAIN AND PLASMA AFTERSINGLE-AND MULTIPLE-DOSE REGIMENS - EVIDENCE FOR ACCUMULATION OF TACRINE IN BRAIN-TISSUE

Tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydra te (THA), Cognex] is a potent acetylcholinesterase inhibitor recently approved for treatment of mild-to-moderate Alzheimer's disease. The po tential for THA and/or a metabolite of THA to accumulate in brain tiss ue was investigated by autoradiographic and metabolic profiling techni ques in rats given single and multiple doses of [C-14]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 anti cholinesterase activity, was also examined. Results from a 16 mg/kg si ngle-dose study showed THA to cross the blood-brain barrier readily an d concentrate in brain tissue, similar to 5-fold compared with plasma. The metabolite 1-OH-THA was found in much lower amounts relative to T HA and when given separately at a similar dose the levels in brain tis sue were comparable with plasma concentrations. After multiple-dose ad ministration, THA concentrations in brain tissue were similar to 3-fol d higher than those achieved after a single oral dose, However, concen tration of 1-OH-THA metabolite increased only 50%, These data suggest a marked difference between the ability of THA and 1-OH-THA to accumul ate in brain tissue and may reflect differences in lipophilicity as es timated by calculated log p values. The relevance of THA accumulation in brain tissue to delays observed in THA clinical management of Alzhe imer's disease remains to be established.