PENETRATION OF TACRINE INTO CEREBROSPINAL-FLUID IN PATIENTS WITH ALZHEIMERS-DISEASE

Tacrine is widely used for the treatment of Alzheimer's disease, but d ata are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheim er's disease who were receiving tacrine at doses of 40 to 140 mg/day a s a part of a double-blind trial were studied. After 6 weeks of tacrin e therapy, concomitant plasma and CSF samples were collected 30 minute s after the morning dose of tacrine. Although this time point is befor e the peak oral absorption in most patients, the critical issue for th is study is that the plasma and CSF samples were collected concomitant ly so that a percentage of tacrine penetration could be derived. The m orning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01 +/- 7. 07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21 +/- 6.0 0 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50 +/- 0.45, with wide interindividual variability. No relation ship between dose and percentage of penetration was observed. Plasma c oncentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dos e, suggesting erratic oral absorption and/or rapid metabolism. CSF con centrations ranged from not detectable to 15.92 ng/mL. The authors sup port that penetration of tacrine into CSF is highly variable in patien ts with Alzheimer's disease and that disparity in tacrine concentratio ns at the site of action may be one reason for conflicting results fro m studies of the efficacy of tacrine in Alzheimer's disease.