Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women.
OBJECTIVE
While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women.


METHODS
Thirty-four, obese (body mass index, BMI > 30 kg m(-2)) women of reproductive age (18-35 years old) were placed on a COC pill containing 20 µg ethinylestradiol/100 µg levonorgestrel for 21 days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21 days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method.


RESULTS
Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3 l h(-1) vs. 53.9 l h(-1), P < 0.05). A median decrease of 5.6 l h(-1) (95% CI -4.1, 13.3 l h(-1)) was observed. However, the magnitude of change was similar to that reported in women with normal BMI.


CONCLUSIONS
Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, USA.
Alison
A
Edelman
Myrna
M
Munar
Miriam R
MR
Elman
Dennis
D
Koop
Ganesh
G
Cherala
D000293:Adolescent; D000328:Adult; D002853:Chromatography, Liquid; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000494:pharmacology*; D008874:Midazolam / Q000493:pharmacokinetics; D009765:Obesity / Q000201:enzymology*; D011446:Prospective Studies; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam