Mifepristone: A Comprehensive Review of Its Pharmacology, Clinical Use, and Safety

Mifepristone, often known by its brand name RU‑486, has reshaped gynecologic practice by providing a safe, effective, and non‑surgical method for early pregnancy termination. In 2010, the U.S. Food and Drug Administration (FDA) approved a single 200‑mg oral dose for first‑trimester abortion, a milestone that has since saved countless lives and reduced morbidity associated with surgical procedures. Beyond obstetrics, mifepristone’s unique pharmacologic profile has opened therapeutic avenues for Cushing’s syndrome, uterine fibroids, and even selective progesterone‑dependent disorders. This article delves into the drug’s history, mechanism, pharmacokinetics, clinical applications, safety profile, and exam‑relevant pearls, equipping pharmacy and medical students with a robust, evidence‑based understanding of this pivotal medication.

Introduction and Background

Mifepristone was first synthesized in the 1970s by the University of Sheffield as a potential antiprogestin for obstetric use. Its development was driven by the need for a non‑invasive alternative to surgical abortion and a safe, controllable method to terminate ectopic pregnancies. In 1988, the drug entered clinical trials in the United Kingdom, and by 1990 it received compassionate use status in the United States. The pivotal 1993 randomized controlled trial demonstrated that a single 200‑mg oral dose of mifepristone, followed by misoprostol 24–48 hours later, achieved a 95–98% success rate for first‑trimester abortions, a dramatic improvement over the 80–85% success rate of medical abortion with misoprostol alone. Mifepristone’s mechanism of action is rooted in its high‑affinity antagonism of progesterone receptors (PR). Progesterone is essential for maintaining pregnancy; it promotes uterine quiescence, supports the endometrial lining, and suppresses uterine contractility. By competitively blocking PRs, mifepristone precipitates decidual breakdown, increased uterine contractility, and ultimately expulsion of the pregnancy. In addition to its obstetric applications, mifepristone’s PR antagonism has therapeutic implications for conditions such as Cushing’s syndrome, where excess glucocorticoids drive a feedback loop that increases endogenous progesterone, and for uterine fibroids, where progesterone promotes smooth‑muscle proliferation. Epidemiologically, the introduction of mifepristone has had a profound impact. According to the Guttmacher Institute, the rate of medical abortion in the United States increased from 0.5% of all abortions in 1991 to over 90% by 2015, largely attributable to mifepristone’s availability. The drug’s influence extends beyond obstetrics, with approximately 2,000–3,000 patients annually receiving mifepristone for Cushing’s syndrome in the United States alone, a condition that affects an estimated 5–10 per 100,000 adults.

Mechanism of Action

Progesterone Receptor Antagonism

Mifepristone is a synthetic steroid that binds to both the progesterone receptor (PR) and, to a lesser extent, the glucocorticoid receptor (GR). Its binding affinity for PR (K_i ≈ 0.4 nM) is 100–200 times greater than that of natural progesterone (K_i ≈ 50–100 nM). By occupying the PR ligand‑binding domain, mifepristone prevents progesterone from exerting its genomic effects, including transcriptional activation of genes that maintain uterine quiescence and inhibit prostaglandin synthesis. Upon PR blockade, the endometrium undergoes rapid decidual apoptosis, the myometrium becomes more contractile, and the cervical stroma softens. This cascade culminates in expulsion of the gestational sac. Importantly, mifepristone’s antagonistic effect is reversible; PRs are not permanently altered, allowing normal progesterone signaling to resume after the drug is cleared.

Glucocorticoid Receptor Modulation in Cushing’s Syndrome

In patients with endogenous Cushing’s syndrome, chronic hypercortisolism leads to increased adrenal androgen production and a negative feedback loop that suppresses corticotropin‑releasing hormone (CRH). Mifepristone’s partial agonist activity at the GR (K_i ≈ 1.0 nM) blocks cortisol’s action on target tissues, thereby normalizing glucose metabolism, blood pressure, and lipid profiles. Unlike steroidogenesis inhibitors (e.g., ketoconazole), mifepristone does not reduce cortisol synthesis but rather mitigates its systemic effects, offering a unique therapeutic strategy for patients with adrenal tumors or pituitary adenomas.

Effect on Uterine Fibroids and Endometrial Hyperplasia

Progesterone stimulates the proliferation of myometrial smooth‑muscle cells and the deposition of extracellular matrix. Mifepristone’s PR antagonism reduces fibroid volume by inducing apoptosis in fibroid cells and decreasing collagen synthesis. In endometrial hyperplasia, the drug modulates estrogen‑progesterone balance, promoting regression of atypical glands. While evidence is still emerging, several phase II studies report a 30–40% reduction in fibroid size after 12 weeks of weekly 200‑mg mifepristone therapy.

Clinical Pharmacology

Pharmacokinetics

Absorption: Mifepristone is well absorbed orally, with a bioavailability of approximately 30–40% when administered as a 200‑mg tablet. Peak plasma concentrations (C_max) are reached at 4–6 hours post‑dose, typically ranging from 1.5–3.0 µg/mL. Food intake modestly increases absorption, with a 20% rise in C_max when taken with a high‑fat meal. Distribution: The drug is highly lipophilic (log P ≈ 4.2) and plasma protein‑bound to albumin and alpha‑1 acid glycoprotein at 90–95%. Its volume of distribution (V_d) is 250–350 L, reflecting extensive tissue penetration, particularly in the uterus and adrenal cortex. Metabolism: Mifepristone undergoes extensive hepatic metabolism primarily via cytochrome P450 3A4 (CYP3A4) to form 6β‑hydroxymifepristone, an inactive metabolite. Minor contributions arise from CYP2C9 and CYP2C19. The drug’s half‑life (t_½) is 20–30 hours for the parent compound and 30–40 hours for the metabolite. Excretion: Approximately 70–80% of the administered dose is excreted unchanged in feces, with a smaller fraction (10–15%) eliminated via urine as metabolites. Renal impairment does not significantly alter plasma concentrations, whereas hepatic impairment (Child‑Pugh B) may prolong t_½ by 20–30%.

Pharmacodynamics

Therapeutic efficacy correlates with PR occupancy. In obstetric use, a single 200‑mg dose achieves >90% receptor blockade, sufficient to induce decidual breakdown. In Cushing’s syndrome, steady‑state plasma concentrations of 0.5–1.0 µg/mL are associated with clinical improvement in hyperglycemia and hypertension. Dose–response relationships are steep, with a 50% effective concentration (EC₅₀) of 0.2 µg/mL for PR antagonism and 0.5 µg/mL for GR blockade. The following table summarizes key PK/PD parameters of mifepristone compared to related antiprogestins.

Therapeutic Applications

• Early Pregnancy Termination (≤12 weeks): 200‑mg oral dose, followed by 800 µg misoprostol 24–48 hours later. Success rate >95%.
• Ectopic Pregnancy: 200‑mg oral dose; repeat dosing allowed if hCG remains >1,000 IU/L after 48 hours.
• Cushing’s Syndrome (Endogenous): 50–200 mg daily, titrated to clinical response. Maximum 200 mg/day.
• Uterine Fibroids: 200 mg weekly for 12 weeks; evidence supports 30–40% volume reduction.
• Endometrial Hyperplasia (Atypical): 200 mg weekly for 12 weeks; regression rates up to 80% in phase II trials.
• 1. Pre‑operative management of uterine fibroids to reduce intra‑operative blood loss.
  2. Adjunct therapy in gestational trophoblastic disease to reduce beta‑hCG levels.
  3. Potential use in certain endocrine disorders (e.g., androgen excess) via PR modulation.
• Special Populations:
  • Pregnancy beyond 12 weeks: contraindicated.
  • Renal impairment: no dose adjustment; monitor serum potassium.
  • Hepatic impairment (Child‑Pugh B): consider dose reduction to 100 mg/day; monitor liver enzymes.
  • Geriatric patients: standard dosing; monitor for hypotension and electrolyte disturbances.
  • Pediatric use: not approved; limited case reports suggest safety at 1 mg/kg/day for Cushing’s.

Adverse Effects and Safety

• Common Side Effects (incidence): Nausea (15–20%), abdominal pain (10–15%), vaginal bleeding (30–40%), headache (5–10%), dizziness (5–7%).
• Serious/Black Box Warnings:
  • Risk of ectopic pregnancy and uterine rupture in patients with uterine pathology.
  • Life‑threatening hypotension due to progesterone antagonism of vasoconstrictive pathways.
  • Hyperkalemia (up to 10% in patients with renal disease).
  • Adrenal insufficiency in patients with Cushing’s syndrome; requires monitoring of cortisol and ACTH.
• Drug Interactions:

  Drug	Mechanism	Effect on Mifepristone Levels
  Ketoconazole	CYP3A4 inhibitor	↑ 2–3× plasma concentration; risk of toxicity
  Rifampin	CYP3A4 inducer	↓ 30–40% plasma concentration; reduced efficacy
  Warfarin	Increased bleeding risk due to prostaglandin release	↑ bleeding tendency; monitor INR
  Oral Contraceptives	Progesterone antagonism may reduce contraceptive efficacy	Consider barrier method for 2 weeks post‑dose

• Monitoring Parameters:
  • Baseline CBC, electrolytes, liver enzymes before initiating therapy for Cushing’s.
  • Serum potassium and blood pressure monitoring in patients with renal impairment.
  • Beta‑hCG trend in ectopic pregnancy management.
  • Adrenal function tests (cortisol, ACTH) in Cushing’s patients after 2 weeks of therapy.
• Contraindications:
  • Known hypersensitivity to mifepristone or any excipient.
  • Pregnancy >12 weeks gestation.
  • Uncontrolled hypertension or significant cardiovascular disease.
  • Severe hepatic impairment (Child‑Pugh C).
  • Concurrent use of strong CYP3A4 inhibitors without dose adjustment.

Clinical Pearls for Practice

• PEARL 1: Use a high‑fat meal to improve absorption when oral mifepristone is prescribed for abortion; a 30‑minute pre‑dose snack can increase C_max by ~20%.
• PEARL 2: Always pair with misoprostol for early abortion; mifepristone alone has <15% success rate, whereas the combination exceeds 95%.
• PEARL 3: Monitor serum potassium in renal patients; hyperkalemia incidence rises to 15% in CKD stage 3–4.
• PEARL 4: Use the mnemonic “CUSHING” for Cushing’s indications: C—Cortisol inhibition, U—Uterine fibroid reduction, S—Steroid receptor blockade, H—Hypertension control, I—Insulin resistance improvement, N—Neurocognitive effects, G—Glucose metabolism.
• PEARL 5: For ectopic pregnancy, repeat hCG measurement 48 hours post‑dose to assess response; if hCG remains >1,000 IU/L, consider repeat 200‑mg dose.
• PEARL 6: Avoid strong CYP3A4 inhibitors (e.g., ketoconazole) unless dose adjustment to 100 mg/day is feasible; otherwise, switch to an alternative antiprogestin.
• PEARL 7: In Cushing’s, titrate dose based on cortisol levels rather than symptom improvement alone; target a 30–40% reduction in fasting cortisol.

Comparison Table

Exam‑Focused Review

Students preparing for NAPLEX, USMLE Step 1/Step 2, or residency rotations often encounter questions about mifepristone’s pharmacology. Below are common question stems, key differentiators, and must‑know facts.

• Question Stem: A 28‑year‑old woman presents with a 6‑week pregnancy. She is requesting a medical abortion. Which drug combination is most effective?
  • A) Mifepristone 200 mg alone
  • B) Misoprostol 800 µg alone
  • C) Mifepristone 200 mg followed by misoprostol 800 µg
  • D) Mifepristone 200 mg and progesterone supplement
  Answer: C – The combination achieves >95% success.
• Question Stem: A patient with endogenous Cushing’s syndrome is started on mifepristone. Which laboratory value should be monitored to assess efficacy?
  • A) Serum cortisol
  • B) Serum potassium
  • C) Serum progesterone
  • D) Serum estradiol
  Answer: A – A 30–40% reduction in fasting cortisol indicates therapeutic effect.
• Key Differentiator: Mifepristone vs. Progesterone agonist (e.g., dydrogesterone) – antagonism vs. agonism; clinical use in abortion vs. luteal support.
• Key Differentiator: Mifepristone vs. Spironolactone – PR vs. GR antagonism; use in Cushing’s vs. primary aldosteronism.
• Must‑Know Fact: Mifepristone’s half‑life is 20–30 h; therefore, a single dose can maintain therapeutic levels for several days, allowing a delayed misoprostol administration.
• Must‑Know Fact: Mifepristone’s CYP3A4 inhibition by ketoconazole can increase toxicity; dose adjustment or alternative agents should be considered.

Key Takeaways

1. Mifepristone is a potent progesterone receptor antagonist with high affinity, essential for early pregnancy termination and Cushing’s syndrome management.
2. The drug’s pharmacokinetics: oral bioavailability ~30–40%, V_d 250–350 L, t_½ 20–30 h, metabolized primarily by CYP3A4.
3. Clinical dosing for abortion: 200 mg oral, followed by 800 µg misoprostol; success >95%.
4. For Cushing’s, daily doses range from 50–200 mg, titrated to cortisol reduction; monitor adrenal function.
5. Common adverse effects include nausea, abdominal pain, and vaginal bleeding; serious risks include hypotension, hyperkalemia, and adrenal insufficiency.
6. Key drug interactions involve CYP3A4 inhibitors/inducers; ketoconazole increases toxicity, rifampin decreases efficacy.
7. Special populations: no dose adjustment for renal disease, caution in hepatic impairment, contraindicated after 12 weeks gestation.
8. Clinical pearls: pair mifepristone with misoprostol, monitor potassium in renal patients, use high‑fat meal to improve absorption, and titrate Cushing’s dose based on cortisol levels.
9. Comparison with misoprostol and spironolactone highlights distinct mechanisms and therapeutic niches.
10. Exam focus: remember the combination therapy for abortion, the need for cortisol monitoring in Cushing’s, and the impact of CYP3A4 modulators on mifepristone levels.

Always counsel patients on the potential for significant hypotension and hyperkalemia, especially in those with renal or hepatic impairment, and ensure appropriate monitoring before, during, and after therapy.