Unpacking the Chemical Identity of Mifepristone
Mifepristone, also known by its developmental code name RU-486, holds a specific and important place in pharmacology [1.2.2]. Its chemical classification is foundational to understanding its mechanism of action and therapeutic applications. Chemically, mifepristone is designated as 11ß-[p-(Dimethylamino)phenyl]-17ß-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one [1.2.1]. It is categorized as a synthetic steroid and, more specifically, a derivative of the 19-nor-steroid family, related to compounds like norethindrone [1.2.1, 1.3.1].
Its structure is derived from steroid hormones such as progesterone and cortisol [1.2.2]. This structural similarity is key to its function. It allows mifepristone to bind to the receptors of these natural hormones, but instead of activating them, it blocks them. This action leads to its functional classifications as a hormone antagonist [1.3.3].
Dual Pharmacological Classification
Mifepristone's primary pharmacological identity is twofold:
- Antiprogestational Steroid (Antiprogestin): Mifepristone is a potent progesterone receptor antagonist [1.3.3, 1.5.5]. It competitively blocks the intracellular progesterone receptors [1.2.4]. Progesterone is a crucial hormone for establishing and maintaining a pregnancy [1.10.1]. By blocking its effects, mifepristone leads to the breakdown of the uterine lining, detachment of the placenta, and cervical softening, which ultimately results in the termination of an early pregnancy [1.5.5, 1.11.4]. This antiprogestational activity is the basis for its use in medical abortion, typically in combination with misoprostol [1.4.3].
- Antiglucocorticoid: At higher doses, mifepristone also acts as a powerful antagonist at glucocorticoid receptors, blocking the effects of cortisol [1.6.1, 1.4.2]. This makes it effective in managing conditions characterized by excess cortisol, such as endogenous Cushing's syndrome [1.6.3]. It helps control hyperglycemia (high blood sugar) in these patients by reducing the effects of excess cortisol, although it does not decrease cortisol production itself [1.4.4, 1.6.3].
Additionally, mifepristone exhibits weak antiandrogenic activity [1.4.4].
A Look at Pharmacokinetics (ADME)
The body's handling of mifepristone—Absorption, Distribution, Metabolism, and Excretion (ADME)—is well-documented:
- Absorption: Mifepristone is absorbed rapidly after oral administration, with peak plasma concentrations reached in about 90 minutes [1.6.1]. The absolute bioavailability of a 20 mg dose is reported to be 69% [1.3.4].
- Distribution: It is highly bound (98%) to plasma proteins, primarily albumin and alpha-1-acid glycoprotein [1.9.4, 1.3.4].
- Metabolism: The liver metabolizes mifepristone, mainly through the CYP3A4 enzyme system [1.3.4]. This process involves N-demethylation and terminal hydroxylation, creating active metabolites that also contribute to the drug's effects [1.3.4, 1.9.4].
- Excretion: Elimination is initially slow, with a half-life of 18 hours, though it can extend up to 90 hours when including all active metabolites [1.9.3, 1.9.4]. The primary route of excretion is through feces (about 83%), with a smaller portion (about 9%) eliminated in urine [1.3.4].
Clinical Applications
The dual antagonist nature of mifepristone leads to two distinct, FDA-approved applications:
- Medical Termination of Pregnancy: Marketed as Mifeprex®, a 200 mg dose is used in combination with misoprostol to terminate an intrauterine pregnancy up to 70 days (10 weeks) of gestation [1.4.3, 1.2.3]. It works by blocking the progesterone necessary to sustain the pregnancy [1.10.1].
- Treatment of Cushing's Syndrome: Under the brand name Korlym®, higher doses (starting at 300 mg) are used to control hyperglycemia in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery [1.2.3, 1.6.2].
Comparison of Progesterone Receptor Modulators
| Feature | Mifepristone | Misoprostol | Ulipristal Acetate |
|---|---|---|---|
| Drug Class | Synthetic Steroid; Progesterone & Glucocorticoid Antagonist [1.2.2, 1.2.1] | Prostaglandin E1 Analog [1.5.5] | Selective Progesterone Receptor Modulator (SPRM) [1.7.3] |
| Mechanism | Blocks progesterone receptors, causing endometrial decay & cervical softening [1.5.5]. | Causes uterine contractions and cervical ripening [1.5.5]. | Binds to progesterone receptors, delaying ovulation (emergency contraception) [1.7.3]. |
| Primary Use | Medical abortion (with misoprostol); Cushing's syndrome [1.2.2]. | Medical abortion (with mifepristone); ulcer prevention. | Emergency contraception; uterine fibroids [1.7.1]. |
| Administration | Oral Tablet [1.2.1] | Buccal or Vaginal Tablet [1.10.3, 1.5.5] | Oral Tablet [1.7.1] |
Conclusion
In summary, the chemical classification of mifepristone is a synthetic 19-nor steroid [1.2.1]. This specific chemical structure allows it to function pharmacologically as a potent antagonist for both progesterone and glucocorticoid receptors [1.2.2]. This dual antagonism defines its clinical utility, enabling it to serve as a critical component in medical abortion regimens and as a targeted therapy for managing the metabolic effects of Cushing's syndrome. Its development in 1980 and subsequent approval in countries like France (1987) and the United States (2000) mark significant milestones in reproductive health and endocrinology [1.2.2].
For more information on the FDA's approved regimen, you can visit the FDA's Q&A page on Mifepristone. [1.4.3]
