Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro.
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Chang SY, Chen C, Yang Z, Rodrigues AD
Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro.
Drug Metab Dispos. 2009 Aug;37(8):1667-75. doi: 10.1124/dmd.109.026997. Epub 2009 May 19.
- PubMed ID
- 19454483 [ View in PubMed]
- Abstract
17alpha-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC(50) (concentration of inhibitor required to decrease activity by 50%) values were obtained with recombinant CYP1A1 (rCYP1A1) [IC(50(total)) = IC(50(free)) = 2.7 microM] and CYP2C19 activity in human liver microsomes (HLM) [IC(50(total)) = 4.4 microM; IC(50(free)) = 2.8 microM]. For rCYP1A1, formal inhibition studies revealed that EE was a competitive inhibitor [K(i(free)) = 1.4 microM]. All the other IC(50) values were greater than 8.0 microM, and the weakest inhibition was observed with CYP1A2 activity in HLM (IC(50(free)) > 39 microM). In agreement, the IC(50) characterizing the inhibition of melatonin (MEL) 6-hydroxylation in human intestine microsomes (CYP1A1-catalyzed) was lower than that of HLM (0.91 versus >40 microM). Because EE is known to affect the pharmacokinetics of CYP2C19 probe drugs, this result raises the possibility that the concentration of EE during first pass may exceed 1000 nM, sufficient to affect CYP1A1 and CYP2C19, with less impact on CYP3A4 and other P450s. The results implicate intestinal CYP1A1, and possibly CYP2C19, as the loci of EE drug interactions with highly extracted drugs like MEL. Overall, it is very difficult to rationalize drug interactions involving EE based on direct inhibition of CYP2B6 (e.g., selegiline) and hepatic CYP1A2 (e.g., MEL, tizanidine, caffeine, and theophylline).
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Estradiol acetate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Estradiol benzoate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Estradiol cypionate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Estradiol dienanthate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Estradiol valerate Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Ethinylestradiol Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareSelegilineDesogestrel The bioavailability of Selegiline can be increased when combined with Desogestrel. SelegilineMegestrol acetate The bioavailability of Selegiline can be increased when combined with Megestrol acetate. SelegilineLevonorgestrel The bioavailability of Selegiline can be increased when combined with Levonorgestrel. SelegilineMedroxyprogesterone acetate The bioavailability of Selegiline can be increased when combined with Medroxyprogesterone acetate. SelegilineNorethisterone The bioavailability of Selegiline can be increased when combined with Norethisterone.