Drug Interactions Involving 17α‐Ethinylestradiol: Considerations Beyond Cytochrome P450 3A Induction and Inhibition

Abstract

It is widely acknowledged that drug‐drug interactions (DDIs) involving estrogen (17α‐ethinylestradiol (EE))‐containing oral contraceptives (OCs) are important. Consequently, sponsors of new molecular entities (NMEs) often conduct clinical studies with priority given to OCs as victims of cytochrome P450 (CYP) 3A (CYP3A) induction and inhibition. Such scenarios are reflected in the US Food and Drug Administration‐issued guidance documentation related to OC DDI studies. Although CYP3A is important, OCs such as EE are metabolized by sulfotransferase 1E1 and UDP‐glucuronosyltransferase (UGT) 1A1, expressed in the gut and liver, and so both can also serve as loci of victim OC DDI. Therefore, for any NME, one should carefully consider its induction and inhibition profile involving CYP3A4/5, UGT1A1, and SULT1E1. As DDI perpetrators, available clinical DDI data indicate that EE‐containing OCs can induce (e.g., UGT1A4 and CYP2A6) and inhibit (CYP1A2 ≥ CYP2C19 > CYP3A4/5 > CYP2C8, CYP2B6, CYP2D6, and CYP2C9) various CYP forms. Although available in vitro CYP inhibition data do not explain such a graded inhibitory effect in vivo, it is hypothesized that EE differentially modulates CYP expression via potent agonism of the estrogen receptor expressed in the gut and liver. From the standpoint of the NME as potential OC DDI victim, therefore, it is important to assess its projected (pre‐phase I) or known therapeutic index and pharmacokinetic profile (fraction absorbed, absolute oral bioavailability, clearance/extraction class, fraction metabolized by CYP1A2, CYP2C19, CYP2A6, and UGT1A4). Such information can enable the prioritization, design, and interpretation of NME‐OC DDI studies.

Combined Oral Contraceptives As Victims of Drug Interactions

“…Despite the recognition that sulfation plays an important role in EE metabolism, the effect of an investigational drug on sulfotransferases (e.g., SULT1E1) is not routinely assessed in in vitro experiments during drug development. A recently published review article also underscores the importance of including SULT1E1 (and UGT1A1) during drug development when evaluating the DDI potential with EE-containing COCs (Rodrigues, 2022). As this is a recently recognized interaction, clinical studies evaluating the impact of SULT inhibition on EE clearance are limited.…”

Attempting to Unmask the Inhibition of Sulfotransferase 1E1 in 17α‐Ethinyl Estradiol Drug Interactions

“…In this regard, EE presents as a DDI victim because it is a sulfotransferase 1E1 (SULT1E1), UDP‐glucuronosyltransferase 1A1 (UGT1A1), and cytochrome P450 3A4 (CYP3A4) substrate. This means that one needs to consider all 3 enzymes when attempting to understand EE DDI 1 . As an example, Helmer et al reported that ziritaxestat (autotaxin inhibitor) significantly impacts the pharmacokinetic (PK) profile of EE 2 .…”

“…It was concluded that the DDI with EE involved SULT1E1 after showing that it was inhibited by ziritaxestat in vitro (half‐maximal inhibitory concentration, IC 50 < 0.8 μ M) (Table 1). Such an approach is logical, because SULT1E1 is expressed in the intestine and liver and plays a major role in EE first‐pass metabolism 1,4 . Of note, ziritaxestat is not the first example of an EE DDI involving SULT1E1 inhibition.…”

“…Schwartz et al have also presented a similar mechanism for etoricoxib (cyclooxygenase‐2 inhibitor) after demonstrating SULT1E1 inhibition in vitro (Table 1). 1,5 Additionally, etoricoxib was considered a weak CYP3A4 inhibitor at the time of the EE DDI study 6,7 …”

Cocktails of NSAIDs and 17α Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally

“…Like natural hormones, synthetic estrogens display estrogenic activity by binding to estrogen receptors a (ESR1) and b (ESR2). They might be more resistant to metabolism and inactivation than the natural hormone 17β-estradiol (E2) (E2) [ 4 , 6 ]. These molecules can cross the placental barrier [ 7 ] and are metabolized in the liver by cytochrome P450-like enzymes, most often producing inactive metabolites [ 8 , 9 ].…”