title: Distribution of tacrine and metabolites in rat brain and plasma after single- and multiple-dose regimens. Evidence for accumulation of tacrine in brain tissue.
abstract: 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.
authors.affiliation: Departments of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Warner-Lambert Company.
authors.forename: W P
authors.initials: WP
authors.lastname: McNally
authors.forename: W F
authors.initials: WF
authors.lastname: Pool
authors.forename: M W
authors.initials: MW
authors.lastname: Sinz
authors.forename: P
authors.initials: P
authors.lastname: Dehart
authors.forename: D F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: C C
authors.initials: CC
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Chang
authors.forename: T F
authors.initials: TF
authors.lastname: Woolf
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine