What is the mechanism of action of mifepristone (RU-486) in medical abortion?

Mechanism of Action of Mifepristone (RU-486)

Mifepristone acts primarily as a selective antagonist of the progesterone receptor, blocking progesterone's effects on the uterus and cervix, while also antagonizing the glucocorticoid receptor at higher doses. 1

Primary Mechanisms

Mifepristone works through several key mechanisms:

1. Progesterone Receptor Antagonism:

   • Binds with high affinity to progesterone receptors (PR-A and PR-B)
   • Blocks progesterone action by preventing gene transcription
   • Prevents recruitment of coactivators, rendering the receptor complex inactive 2
   • Competes directly with progesterone at binding sites 1

2. Glucocorticoid Receptor Antagonism:

   • At higher doses, blocks glucocorticoid receptor (GR-II) 1
   • Has high affinity for GR-II but little affinity for GR-I (mineralocorticoid) receptor 1
   • Shows greater receptor affinity (100%) than dexamethasone (23%) or cortisol (9%) 1

3. Pharmacological Properties:

   • Orally active with peak plasma concentrations between 1-2 hours after single dose 1
   • Half-life of approximately 85 hours following multiple doses 1
   • Highly bound to alpha-1-acid glycoprotein and albumin (99.2% protein binding) 1
   • Metabolized primarily by CYP3A4 in the liver 1
   • Excreted primarily (90%) via the fecal route 1

Effects in Medical Abortion

When used for medical abortion, mifepristone:

1. Uterine Effects:

   • Blocks progesterone's action, which is necessary to sustain pregnancy 3
   • Increases uterine sensitivity to prostaglandins 2
   • Causes decidual breakdown 4

2. Cervical Effects:

   • Promotes cervical softening and dilation 5
   • Facilitates expulsion of pregnancy tissue when combined with prostaglandins 3

3. Endocrine Effects:

   • Inhibits the pituitary gland's luteinizing hormone surge 2
   • Results in anovulation and subsequent amenorrhea 2

Clinical Application in Medical Abortion

For medical abortion, mifepristone is typically:

• Used in combination with misoprostol (a prostaglandin analog)
• Effective for termination of pregnancies up to 9 weeks gestation
• FDA-approved for induced abortions of gestations of 49 days or less since the last menstrual period 3

Important Considerations

• Mifepristone has high specificity - little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors 1
• Food significantly increases plasma levels of mifepristone, so consistent administration with meals is important for stable drug concentrations 1
• The drug crosses the blood-brain barrier and is distributed to the central nervous system 1

Mifepristone's unique dual antagonism of progesterone and glucocorticoid receptors has led to investigation of its use in other conditions beyond abortion, including contraception, treatment of uterine fibroids, and management of certain gynecologic cancers 5, 6.