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Mifepristone (RU486)

The search for a glucocorticoid receptor antagonist finally succeeded in the early 1980s with the development of the 11β-aminophenyl-substituted 19-norsteroid called RU486, later named mifepristone.

This compound has strong anti-progestin activity and initially was proposed as a contraceptive contragestive agent.

High doses of mifepristone exert anti-glucocorticoid activity by blocking the glucocorticoid receptor, since mifepristone binds to it with high affinity, causing (1) some stabilization of the heat-shock-protein(HSP)-glucocorticoid receptor complex and, thus inhibition of the dissociation of the RU486-bound glucocorticoid receptor from the HSP chaperone proteins; and (2) alteration of the interaction of the glucocorticoid receptor with co-regulators, favoring the formation of a transcriptionally inactive complex in the cell nucleus.

The result is inhibition of glucocorticoid receptor activation.

The mean half-life of mifepristone is 20 hours.

This is longer than that of many natural and synthetic glucocorticoid agonists (dexamethasone has a half-life of 4~5 hours).

Less than 1% of the daily dose is excreted in the urine, suggesting a minor role of kidneys in the clearance of the compound.

The long plasma half-life of mifepristone results from extensive and strong binding to plasma proteins.

Less than 5% of the compound is found in the free form when plasma is analyzed by equilibrium dialysis.

Mifepristone can bind to albumin and α1-acid glycoprotein, but it has no affinity for corticosteroid-binding globulin (CBG).

In humans, mifepristone causes generalized glucocorticoid resistance.

Given orally to several patients with Cushing’s syndrome due to ectopic ACTH production or adrenal carcinoma, it was able to reverse the cushingoid phenotype, to eliminate carbohydrate intolerance, normalize blood pressure, correct thyroid and gonadal hormone suppression, and ameliorate the psychologic sequelae of hypercortisolism in these patients.

To date, the application of mifepristone can only be recommended for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapeutic manipulations.

Mifepristone (RU486) is a “19-norsteroid” that binds strongly to the progesterone receptor and inhibits the activity of progesterone.

The drug has luteolytic properties in 80% of women when given in the midluteal period.

The mechanism of this effect is unknown, but it may provide the basis for using mifepristone as a contraceptive (as opposed to an abortifacient).

However, because the compound has a long half-life, large doses may prolong the follicular phase of the subsequent cycle and so make it difficult to use continuously for this purpose.

A single dose of 600mg is an effective emergency postcoital contraceptive, though it may result in delayed ovulation in the following cycle.

Mifepristone’s major use thus far has been to terminate early pregnancies.

Doses of 400~600mg/day for 4 days or 800mg/day for 2 days successfully terminated pregnancy in over 85% of the women studied. The major adverse effect was prolonged bleeding that on most occasions did not require treatment.

The combination of a single oral dose of 600mg of mifepristone and a vaginal pessary containing 1 mg of prostaglandin E1 or oral misoprostol has been found to effectively terminate pregnancy in over 95% of patients treated during the first 7 weeks after conception.

The adverse effects of the medications included vomiting, diarrhea, and abdominal or pelvic pain.

As many as 5% of patients have vaginal bleeding requiring intervention.

Because of these adverse effects, RU486 is administered only by physicians at family planning centers.

ZK98734 (lilopristone) is a potent experimental progesterone inhibitor and abortifacient in doses of 25mg twice daily.

Like mifepristone, it also appears to have anti-glucocorticoid activity.