title: The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.
abstract: BACKGROUND
  Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin.
  
  
  OBJECTIVE
  The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin.
  
  
  RESULTS
  Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin.
  
  
  CONCLUSIONS
  In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD., USA.
authors.forename: P
authors.initials: P
authors.lastname: Barditch-Crovo
authors.forename: C B
authors.initials: CB
authors.lastname: Trapnell
authors.forename: E
authors.initials: E
authors.lastname: Ette
authors.forename: H A
authors.initials: HA
authors.lastname: Zacur
authors.forename: J
authors.initials: J
authors.lastname: Coresh
authors.forename: L E
authors.initials: LE
authors.lastname: Rocco
authors.forename: C W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: C
authors.initials: C
authors.lastname: Flexner
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D003278:Contraceptives, Oral, Hormonal / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009640:Norethindrone / Q000493:pharmacokinetics*; D011446:Prospective Studies; D017828:Rifabutin / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D000904:Antibiotics, Antitubercular; D003278:Contraceptives, Oral, Hormonal; D004791:Enzyme Inhibitors; D017828:Rifabutin; D004997:Ethinyl Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D005723:gamma-Glutamyltransferase; D009640:Norethindrone; D012293:Rifampin