The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone.
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Hendrix CW, Jackson KA, Whitmore E, Guidos A, Kretzer R, Liss CM, Shah LP, Khoo KC, McLane J, Trapnell CB
The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone.
Clin Pharmacol Ther. 2004 May;75(5):464-75. doi: 10.1016/j.clpt.2004.01.003.
- PubMed ID
- 15116059 [ View in PubMed]
- Abstract
BACKGROUND: Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated. METHODS: We enrolled 26 healthy women who were to receive isotretinoin for the treatment of severe, recalcitrant nodular acne and who were taking or planning to take oral contraceptives. The pharmacokinetics of ethinyl estradiol and norethindrone (INN, norethisterone) (the components of Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of 2 separate oral contraceptive cycles, before and during isotretinoin treatment. RESULTS: The addition of isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, although statistically significant (P <.04), decreases in the concentrations of both ethinyl estradiol (9% decrease in area under the plasma concentration-time curve from time 0 to 24 hours after the dose on day 6) and norethindrone (11% decrease in maximum plasma concentration on day 20). Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers, although a majority of women had increases in these measures. Although there was no correlation between isotretinoin (or metabolite) levels and oral contraceptive levels (P >.05), there was a correlation between progesterone level and oral contraceptive levels (P <.05). Variability was large for both pharmacokinetic measures (median coefficients of variation of 44%-69% [for each time point within a study period]) and pharmacodynamic measures (median coefficients of variation of 64%-114%). One woman in each study phase, one before and one during isotretinoin treatment, had a progesterone elevation consistent with possible ovulation. No serious or unexpected adverse events were observed. CONCLUSIONS: The small reduction in ethinyl estradiol and norethindrone levels associated with isotretinoin was not associated with any pharmacodynamic changes in our study. The combination of the teratogenic risk of isotretinoin and the large variability of and correlation between oral contraceptive levels and pharmacodynamic measures, however, strongly reinforces the necessity of additional contraceptive methods during concomitant administration of these drugs.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Isotretinoin Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareCyproterone acetateVitamin A The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Vitamin A. Cyproterone acetateBexarotene The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Bexarotene. Cyproterone acetateAlitretinoin The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Alitretinoin. Cyproterone acetateTretinoin The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Tretinoin. Cyproterone acetateTazarotene The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Tazarotene.