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-life 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.
Forgue
S T
ST
Pharmacokinetics/Drug Metabolism Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Reece
P A
PA
Sedman
A J
AJ
deVries
T M
TM
D000368:Aged; D000704:Analysis of Variance; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D002927:Cimetidine / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013619:Tacrine / Q000097:blood / Q000493:pharmacokinetics*
D002800:Cholinesterase Inhibitors; D006635:Histamine H2 Antagonists; D013619:Tacrine; D002927:Cimetidine