Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation.
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.
Palovaara
Sanna
S
Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland. sanna.palovaara@utu.fi
Pelkonen
Olavi
O
Uusitalo
Jouko
J
Lundgren
Stefan
S
Laine
Kari
K
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
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