The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity

Donna J. Belle, John Callaghan, J. Christopher Gorski, Juan F. Maya, Omiema Mousa, Steven A. Wrighton, Stephen D. Hall

Research output: Contribution to journalArticle

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Abstract

Aims: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. Methods: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg-1) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral™ (50 μg ethinyloestradiol/500 μg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. Results: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,∞)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,∞)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral™ for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = - 0.936). Conclusions: Administration of Ovral™ for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalBritish Journal of Clinical Pharmacology
Volume53
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Norgestrel
Cytochrome P-450 CYP3A
Ethinyl Estradiol
Midazolam
Oral Contraceptives
Ethinyl Estradiol-Norgestrel Combination
Area Under Curve
Liver
Liquid Chromatography
Intravenous Administration
Oral Administration
Half-Life
Mass Spectrometry

Keywords

  • CYP3A
  • Ethinyloestradiol
  • Midazolam
  • Norgestrel

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. / Belle, Donna J.; Callaghan, John; Gorski, J. Christopher; Maya, Juan F.; Mousa, Omiema; Wrighton, Steven A.; Hall, Stephen D.

In: British Journal of Clinical Pharmacology, Vol. 53, No. 1, 2002, p. 67-74.

Research output: Contribution to journalArticle

Belle, Donna J. ; Callaghan, John ; Gorski, J. Christopher ; Maya, Juan F. ; Mousa, Omiema ; Wrighton, Steven A. ; Hall, Stephen D. / The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. In: British Journal of Clinical Pharmacology. 2002 ; Vol. 53, No. 1. pp. 67-74.
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AU - Callaghan, John

AU - Gorski, J. Christopher

AU - Maya, Juan F.

AU - Mousa, Omiema

AU - Wrighton, Steven A.

AU - Hall, Stephen D.

PY - 2002

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N2 - Aims: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. Methods: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg-1) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral™ (50 μg ethinyloestradiol/500 μg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. Results: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,∞)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,∞)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral™ for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = - 0.936). Conclusions: Administration of Ovral™ for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.

AB - Aims: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. Methods: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg-1) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral™ (50 μg ethinyloestradiol/500 μg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. Results: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,∞)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,∞)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral™ for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = - 0.936). Conclusions: Administration of Ovral™ for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.

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