Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation

Clin Pharmacol Ther. 2003 Oct;74(4):326-33. doi: 10.1016/S0009-9236(03)00202-9.


Aim: Our objective was to study the effect of hormone replacement therapy and a combination oral contraceptive on the cytochrome P450 (CYP) 2B6 activity with bupropion (INN, amfebutamone) hydroxylation used as a probe reaction.

Methods: This was a 3-way crossover study with 12 healthy female volunteers. The first phase was a control phase, in which all subjects received a single 150-mg dose of bupropion (sustained release) without pretreatment. In the second and third phases, in randomized balanced crossover order, subjects received a 10-day pretreatment with either hormone replacement therapy, containing 2 mg estradiol valerate and 250 microg levonorgestrel, or an oral contraceptive, containing 30 microg ethinyl estradiol (INN, ethinylestradiol) and 150 microg desogestrel, and the bupropion dose was given 1 hour after the last hormone dose. The bupropion, hydroxybupropion, and hydrobupropion plasma concentrations were determined for up to 72 hours.

Results: The 10-day hormone replacement therapy pretreatment reduced the hydroxybupropion/bupropion area under the plasma concentration-time curve (AUC) ratio by 49% (P <.001; 95% confidence interval [CI], -58% to -40%) as a result of a marked 47% decrease (P <.001; 95% CI, -54% to -41%) in the AUC of hydroxybupropion. Moreover, the AUC of hydrobupropion was significantly (64%; P =.003; 95% CI, 22% to 106%) increased. The AUC of hydroxybupropion was also reduced after the oral contraceptive treatment but to a lesser extent (-31%; P <.001; 95% CI, -37% to -26%). However, the hydroxybupropion/bupropion AUC ratio was not significantly affected.

Conclusions: Hormone replacement therapy markedly inhibited the CYP2B6-catalyzed hydroxylation of bupropion, whereas a combination oral contraceptive had only a modest effect on CYP2B6 activity. Patients receiving hormone replacement therapy or oral contraceptives may need dose adjustment when treated with drugs metabolized by CYP2B6.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases* / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases* / metabolism
  • Bupropion / blood
  • Bupropion / metabolism
  • Bupropion / pharmacokinetics*
  • Contraceptives, Oral / pharmacology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2B6
  • Desogestrel / pharmacology
  • Dopamine Uptake Inhibitors / blood
  • Dopamine Uptake Inhibitors / metabolism
  • Dopamine Uptake Inhibitors / pharmacokinetics*
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Ethinyl Estradiol / pharmacology
  • Female
  • Half-Life
  • Hormone Replacement Therapy*
  • Humans
  • Hydroxylation / drug effects
  • Levonorgestrel / pharmacology
  • Metabolic Clearance Rate
  • Oxidoreductases, N-Demethylating* / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating* / metabolism


  • Contraceptives, Oral
  • Dopamine Uptake Inhibitors
  • Bupropion
  • Ethinyl Estradiol
  • Estradiol
  • Levonorgestrel
  • Desogestrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating