Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacology

Background:

• In vitro studies suggest synthetic hormones in hormone replacement therapy (HRT) inhibit oxidative drug metabolism.
• HRT has been linked to enhanced tacrine response in postmenopausal Alzheimer's disease patients, but the mechanism is unclear.

Purpose of the Study:

• To investigate the pharmacokinetic interaction between HRT (estradiol valerate and levonorgestrel) and tacrine.
• To determine how HRT affects tacrine absorption, distribution, metabolism, and excretion.

Main Methods:

• A randomized, double-blind, crossover study involving 10 healthy female volunteers.
• Participants received daily HRT or placebo for 10 days, followed by a single 40-mg dose of tacrine.
• Plasma and urine samples were collected over 30 and 24 hours, respectively, to measure tacrine and its metabolite, 1-hydroxytacrine.

Main Results:

• HRT significantly increased tacrine's mean plasma area under the concentration-time curve (AUC) by 60% and peak concentration by 46%.
• HRT reduced tacrine's oral clearance by 31% but did not significantly alter its elimination half-life or renal clearance.
• The metabolic ratio of 1-hydroxytacrine to tacrine was significantly reduced by 26% in all subjects.

Conclusions:

• HRT with estradiol and levonorgestrel significantly elevates plasma tacrine levels.
• The interaction is attributed to reduced CYP1A2-mediated first-pass metabolism of tacrine to 1-hydroxytacrine.
• This interaction may necessitate dose adjustments of tacrine in Alzheimer's patients receiving HRT to balance efficacy and safety.