title: Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland. sanna.palovaara@utu.fi
authors.forename: Sanna
authors.initials: S
authors.lastname: Palovaara
authors.forename: Olavi
authors.initials: O
authors.lastname: Pelkonen
authors.forename: Jouko
authors.initials: J
authors.lastname: Uusitalo
authors.forename: Stefan
authors.initials: S
authors.lastname: Lundgren
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016642:Bupropion / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D003276:Contraceptives, Oral / Q000494:pharmacology*; D018592:Cross-Over Studies; D065702:Cytochrome P-450 CYP2B6; D017135:Desogestrel / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D020249:Hormone Replacement Therapy; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D016912:Levonorgestrel / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003276:Contraceptives, Oral; D018765:Dopamine Uptake Inhibitors; D016642:Bupropion; D004997:Ethinyl Estradiol; D004958:Estradiol; D016912:Levonorgestrel; D017135:Desogestrel; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating