Inhibition of tacrine oral clearance by cimetidine

Plasma tacrine, 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine concentrations were measured in 12 healthy elderly subjects in this nonblinded two-period study to assess the effect of multiple doses of cimetidine on single-dose tacrine pharmacokinetics, Subjects received 40 mg tacrine (Cognex) alone and during multiple dose cimetidine (300 mg four times a day) administration, Overall, tacrine and cimetidine were well tolerated by healthy elderly subjects, After coadministration of cimetidine with tacrine, plasma tacrine concentrations were approximately one-third higher than values after administration of tacrine alone; metabolite concentrations were also higher. Mean tacrine oral clearance was reduced by 30%; however, mean absorption rate and elimination half-lift values were not affected by cimetidine, It was concluded that cimetidine inhibits first-pass hepatic extraction of tacrine by cytochrome P450 enzymes but has little effect on systemic drug clearance, Clinical considerations may dictate a reduction in tacrine dosage when tacrine is coadministered with cimetidine.