Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy

Background: In vitro results suggest that the synthetic hormones used in po stmenopausal hormone replacement therapy (HRT) may be significant inhibitor s of oxidative drug metabolism. Moreover, HRT has been reported to enhance response to tacrine in postmenopausal patients with Alzheimer's disease, bu t 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. On e hour after the last HRT or placebo capsule on day 10, the subjects receiv ed a single 40-mg dose of tacrine. Plasma samples were collected for 30 hou rs and urine samples were collected for 24 hours after tacrine intake for t he 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 indi vidual increase in the AUC was about threefold, Similarly, the mean peak co ncentration in plasma of tacrine was 46% (P = .031) higher in the HRT phase compared with the placebo phase. HRT reduced the mean apparent oral cleara nce of tacrine by 31% (P = .014), but no significant difference was found i n the elimination half-life or the renal clearance of tacrine between the H RT phase and the placebo phase. The metabolic ratio (1-hydroxytacrine AUC/t acrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subje cts. Conclusions: HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT inv olves reduced metabolic conversion of tacrine to its main metabolite 1-hydr oxytacrine by CYP1A2 during the first-pass phase. The interaction may be cl inically important with regard to both enhanced efficacy and increased like lihood of concentration-dependent adverse effects of tacrine in the long-te rm treatment of patients with Alzheimer's disease, Accordingly, smaller dos es of tacrine may be appropriate when coadministered with HRT.