The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.
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.
Barditch-Crovo
P
P
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD., USA.
Trapnell
C B
CB
Ette
E
E
Zacur
H A
HA
Coresh
J
J
Rocco
L E
LE
Hendrix
C W
CW
Flexner
C
C
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
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