PT  - JOURNAL ARTICLE
AU  - Li Li
AU  - Xinning Yang
AU  - Doanh Tran
AU  - Shirley K Seo
AU  - Yanhui Lu
TI  - <strong><strong>Combined oral contraceptives as victims of drug interactions</strong></strong>
AID  - 10.1124/dmd.122.000854
DP  - 2023 Jan 01
TA  - Drug Metabolism and Disposition
PG  - DMD-MR-2022-000854
4099  - http://dmd.aspetjournals.org/content/early/2023/03/24/dmd.122.000854.short
4100  - http://dmd.aspetjournals.org/content/early/2023/03/24/dmd.122.000854.full
AB  - Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs, known interactions of these COCs as victim drugs, and discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs. Significance Statement This minireview provides an overview of the metabolic pathways of ethinyl estradiol (EE) and progestins contained in commonly used COCs and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, and future perspectives and provides insights on potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.