The interaction between St John's wort and an oral contraceptive.
OBJECTIVE
The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone).


METHODS
Twelve healthy premenopausal women who were using oral contraception (>3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles.


RESULTS
Concomitant use of St John's wort was associated with a significant (P <.05) increase in the oral clearance of norethindrone (8.2 +/- 2.7 L/h to 9.5 +/- 3.4 L/h, P =.042) and a significant reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023). The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3 L/h, P =.007) during St John's wort administration, but the systemic clearance of midazolam was unchanged (37.7 +/- 11.3 L/h to 39.0 +/- 10.3 L/h, P =.567). Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St John's wort dosing (P >.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005).


CONCLUSIONS
St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort.
Hall
Stephen D
SD
Division of Clinical Pharmacology, Department of Medicine, Myers Building, W7123, Wishard Hospital, 1001 W 10th St, Indianapolis, IN 46202-2879, USA. sdhall@iupui.edu
Wang
Zaiqi
Z
Huang
Shiew-Mei
SM
Hamman
Mitchell A
MA
Vasavada
Nina
N
Adigun
Adegboyega Q
AQ
Hilligoss
Janna K
JK
Miller
Margaret
M
Gorski
J Christopher
JC
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000378:metabolism; D003277:Contraceptives, Oral, Combined / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D004338:Drug Combinations; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006207:Half-Life; D006801:Humans; D020902:Hypericum; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008597:Menstrual Cycle / Q000187:drug effects; D008656:Mestranol / Q000378:metabolism* / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics*; D009640:Norethindrone / Q000378:metabolism* / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000378:metabolism; D028321:Plant Preparations / Q000008:administration & dosage / Q000494:pharmacology*
D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D006993:Hypnotics and Sedatives; D028321:Plant Preparations; C014715:Norinyl; D005640:Follicle Stimulating Hormone; D008656:Mestranol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D009640:Norethindrone