In a previous pharmacokinetic study in Alzheimer patients great inter-individual 
variation and low oral bioavailability of the cholinesterase inhibitor tacrine 
(tetrahydroaminoacridine, THA) were found. In the present investigation oral and 
rectal administration of tacrine were compared with the aim to find a route for 
improved bioavailability through diminished first-pass metabolism in the liver. 
Eight patients suffering from Alzheimer's dementia were given tacrine by oral 
(25 and 50 mg b.i.d.) and rectal (12.5 and 25 mg b.i.d.) routes for 1 week with 
4-6 weeks washout in between. Drug hydroxylation capacity in the patients was 
determined using the debrisoquine test. Levels of tacrine in plasma and 
cerebrospinal fluid (CSF) were determined and the cognitive performance was 
examined by the Mini-Mental State Examination (MMSE) and the Alzheimer Deficit 
Assessment Scale (ADAS). Tacrine was well tolerated in all but one patient, a 
slow hydroxylator, who developed an aplastic anemia. MMSE and ADAS scores did 
not significantly change, except for word recall which was improved on tacrine 
when given by the rectal route. Pharmacokinetic analysis of the two 
administration routes revealed that the drug dose may be reduced by almost 50% 
when given rectally compared to orally. Concentrations of tacrine in the CSF 
were significantly lower and correlated linearly with the concentrations in 
plasma.