Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy.
BACKGROUND
In vitro results suggest that the synthetic hormones used in postmenopausal hormone replacement therapy (HRT) may be significant inhibitors of oxidative drug metabolism. Moreover, HRT has been reported to enhance response to tacrine in postmenopausal patients with Alzheimer's disease, but the mechanism of this interaction remains unclear.


OBJECTIVE
To examine the effect of HRT with 2 mg estradiol valerate and 0.25 mg levonorgestrel once daily on the pharmacokinetics of tacrine.


METHODS
Ten healthy female volunteers received treatment for 10 days with once-daily HRT or placebo in a randomized, double-blind crossover study. One hour after the last HRT or placebo capsule on day 10, the subjects received a single 40-mg dose of tacrine. Plasma samples were collected for 30 hours and urine samples were collected for 24 hours after tacrine intake for the measurement of tacrine and 1-hydroxytacrine concentrations.


RESULTS
HRT increased the mean plasma concentration-time curve calculated from zero to infinity (AUC) of tacrine by 60% (P = .009); the greatest individual increase in the AUC was about threefold. Similarly, the mean peak concentration in plasma of tacrine was 46% (P = .031) higher in the HRT phase compared with the placebo phase. HRT reduced the mean apparent oral clearance of tacrine by 31% (P = .014), but no significant difference was found in the elimination half-life or the renal clearance of tacrine between the HRT phase and the placebo phase. The metabolic ratio (1-hydroxytacrine AUC/tacrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subjects.


CONCLUSIONS
HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT involves reduced metabolic conversion of tacrine to its main metabolite 1-hydroxytacrine by CYP1A2 during the first-pass phase. The interaction may be clinically important with regard to both enhanced efficacy and increased likelihood of concentration-dependent adverse effects of tacrine in the long-term treatment of patients with Alzheimer's disease. Accordingly, smaller doses of tacrine may be appropriate when coadministered with HRT.
Laine
K
K
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. karlai@utu.fi
Palovaara
S
S
Tapanainen
P
P
Manninen
P
P
D000328:Adult; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D016912:Levonorgestrel / Q000494:pharmacology*; D018697:Nootropic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D045167:Progesterone Congeners / Q000494:pharmacology*; D012016:Reference Values; D013619:Tacrine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D045167:Progesterone Congeners; D004958:Estradiol; D013619:Tacrine; D016912:Levonorgestrel; D019388:Cytochrome P-450 CYP1A2; C056424:velnacrine