The unique pharmacological characteristics of mifepristone (RU486): from terminating pregnancy to preventing cancer metastasis.

Mifepristone (RU486) is a born-for-woman molecule discovered three decades ago. Unlike those antihypertensive and antipsychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential. Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing our views on the drug beyond its abortifacient scope. Here we briefly review its metabolism and pharmacokinetic properties including its unique enterohepatic circulation, its mechanisms of actions involving antiprogesterone and antiglucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, downregulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration. We comprehensively analyze recent results from preclinical and clinical studies using mifepristone as an anticancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma. Although mifepristone has more benefits for global public health than we originally thought, its effect as a postmetastatic chemotherapeutic agent is limited. Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention.

Medical abortion in lactating women--low levels of mifepristone in breast milk.

OBJECTIVE: Medical abortion using mifepristone followed by misoprostol is increasingly used for termination of an unwanted pregnancy. Consequently, an increasing number of women undergo medical abortion while still breastfeeding from a previous pregnancy. But there are no data on mifepristone use during lactation. We studied the levels of mifepristone in breast milk collected from women undergoing medical abortion. DESIGN AND SAMPLES: Samples of milk were collected from 12 women during the first 7 days after intake of either 200 mg (n = 2) or 600 mg (n = 10) of mifepristone. In addition, serum samples were collected on day 3 (n = 4). Main outcome measures. The levels of mifepristone, quantified using radioimmunoassay. RESULTS: The milk concentrations of mifepristone were highest in the first samples collected during the first 12 hours following drug intake, and ranged from undetectable (< 0.013 micromol/l) to 0.913 micromol/l. Thereafter, declining concentrations of mifepristone were detected up to 7 days. The lowest levels of mifepristone in milk were measured following ingestion of the 200 mg dose. The milk:serum ratio of mifepristone ranged from < 0.013:1 to 0.042:1 on day 3 (n = 4). The calculated relative infant dose (RID) was 1.5% at its highest. CONCLUSIONS: The levels of mifepristone in milk are low, especially when using the 200 mg dose. Breastfeeding can be safely continued in an uninterrupted manner during medical abortion of this kind.

[Pharmacokinetics of mifepristone and kinetics of chorionic gonadotropin beta-subunit (beta-HCG) and progesterone in plasma of pregnant women during pharmacological interruption of early pregnancy]. / Farmakinetika mifepristona i kinetika beta-sub''edinitsy khorionicheskogo gonadotropina (beta-KhG) i progesterona v plazme krovi beremennykh zhenshchin pri medikamentoznom preryvanii rannei beremennosti.

Reliable correlations between the parameters of mifepriston pharmacokinetics describing the rate of drug elimination from the blood plasma and the levels of beta-human chorionic gonadotropin (beta-HCG) and progesterone reflecting the state of gestation in females have been established fore the first time. According to these relationships, the half elimination time, the mean retention time, and the plasma clearance of mifepriston can be considered as predictors of the clinical efficacy of this drug for the early pregnancy interruption.

Mifepristone: bioavailability, pharmacokinetics and use-effectiveness.

The potentiality of mifepristone as an abortifacient and contraceptive drug along with its pharmacokinetic parameters is reviewed. Mifepristone or RU486 acts as antagonist to progestational and glucocorticoid functions. It is an orally active compound with nearly 70% absorption rate but its bioavailability is reduced to around 40% because of the first-pass effect. Peak plasma concentrations of 1.9 +/- 0.8, 3.8 +/- 0.9 and 5.3 +/- 1.3 micromol/l are reached within 1-2 h after oral administration of 50, 200 and 600 mg mifepristone in women, respectively, and are maintained at relatively high level up to 48 or 72 h depending on the ingested dose. The plasma kinetics of mifepristone followed two-compartment open model with a mean alpha-half-life of 1.4h, volume of distribution 1.47 l/kg and beta-half-life of 20-30 h in most of the subjects studied. Clearance from the body was mainly through feces (83%). Biologically active mono-demethylated, di-demethylated and hydroxylated metabolites were found in plasma soon after oral administration of mifepristone. RU486 and its mono-demethylated metabolite bind to progesterone receptors with high affinity. Mifepristone-bound receptor dimers suppress transcription activation and thus, bring about anti-progestational activity that makes mifepristone a potential abortifacient and contraceptive agent. Clinical trials for termination of early pregnancy with 50-600 mg mifepristone plus a prostaglandin analogue achieved a success rate of 82-97%. However, abdominal pain, cramping, nausea, vomiting, bleeding and delay in onset of the next menstrual cycle were the side effects. Administration of 25 mg mifepristone twice 12h apart, as a post-coital contraceptive showed 100% contraceptive efficacy. A low dose of mifepristone which does not inhibit ovulation reduced fertility significantly by affecting endometrial milieu. These findings suggest that reduced dose(s) of mifepristone, 200 mg or less, may be used as a post-coital contraceptive and in combination with vaginal misoprostol for termination of early pregnancy with high efficacy and minimal or no side effects.

Mifepristone.

OBJECTIVE: To review the efficacy and safety of mifepristone (with misoprostol) for the termination of early pregnancy. DATA SOURCES: A MEDLINE search (1966-October 2000) was conducted, and additional references listed in articles were included; unpublished data obtained from the manufacturer were used to identify data from the scientific literature. Studies evaluating mifepristone were considered for inclusion. STUDY SELECTION: Human clinical studies in the English language were reviewed and evaluated. Clinical trials selected for detailed review were limited to those including the regimens of mifepristone and misoprostol, recently approved by the Food and Drug Administration for early pregnancy termination. DATA SYNTHESIS: Mifepristone is an antiprogestin available for pregnancy termination in combination with a prostaglandin such as misoprostol. Mifepristone offers efficacy similar to, if not better than, other drugs used for pregnancy termination, but appears less efficacious overall than surgical termination of pregnancy. Mifepristone in combination with misoprostol commonly causes adverse effects such as abdominal pain and, less commonly, can cause serious adverse effects such as incomplete abortion; endometritis; and bleeding warranting transfusion, hospitalization, or surgery. Mifepristone is metabolized by the cytochrome P450 system. Thus, the potential for drug interactions with this agent exists, although this has not been well studied. Data are included from clinical trials evaluating the safety, tolerability, efficacy, and pharmacoeconomics of mifepristone combined with misoprostol for early pregnancy termination. Data comparing the use of these agents with surgical abortion and other drugs used for pregnancy termination are included where available. CONCLUSIONS: Mifepristone in combination with misoprostol for the termination of early pregnancy (amenorrhea of < or = 49 d) is effective in 92-95% of women. Incomplete abortion requiring surgical abortion after the fact occurs in 3-5% of women, and pregnancy continues 1-2% of the time. Mifepristone with misoprostol treatment is not without significant risks, including hemorrhage, infection, and potential for long-term emotional consequences.

Mifepristone (RU 486): current knowledge and future prospects.

Mifepristone (RU 486) has received recent attention for its effects as an abortifacient. Mifepristone has not yet been approved for use in the United States. The Food and Drug Administration issued an "approvable letter" in September 1996, but mifepristone will not be available in the United States until a new manufacturer is found. Experience with mifepristone is extensive in Europe, and there have been retrospective studies and large, controlled clinical trials of its efficacy. It is most efficacious when administered to women who are less than 8 weeks pregnant, in a single 600-mg oral dose followed 48 hours later by administration of intravaginal misoprostol. This regimen has a success rate of 98%, as do most surgical abortive procedures. The most frequent adverse effect is painful contractions, which occur in up to 93% of women, with oral analgesia required in as many as half the cases. Large-scale surveys of women who elected medical abortion reported high patient satisfaction. Mifepristone is likely to have additional clinical uses. Researchers are exploring mifepristone's potential uses in cervical ripening and labor induction; contraception; delivery after intrauterine demise; treatment of breast cancer, unresectable meningioma, and prostate cancer; amelioration of endometriosis; and management of Cushing syndrome.

Clinical pharmacokinetics of mifepristone.

Mifepristone is a steroidal antiprogestin and antiglucocorticoid acting at the receptor level. The aromatic dimethylaminophenyl side chain in position 11 of the steroid structure is essential for the antagonistic properties of mifepristone. The pharmacokinetics of mifepristone are characterised by rapid absorption, a long half-life of 25 to 30 hours and micromolar serum concentrations following ingestion of doses currently in clinical use. The serum transport protein alpha 1-acid glycoprotein (AAG) regulates the serum kinetics of mifepristone. Binding to AAG limits the tissue availability of mifepristone, explaining the low metabolic clearance rate of 0.55 L/kg/day and the low volume of distribution of mifepristone. Also, similar serum concentrations of mifepristone following ingestion of single doses exceeding 100mg can be explained by saturation of the binding capacity of serum AAG. Following oral intake, mifepristone is extensively metabolised by demethylation and hydroxylation, the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4. The 3 most proximal metabolites, namely the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward the human progesterone and glucocorticoid receptors; in addition, the serum concentrations of these 3 metabolites are in a similar range as those of the parent drug. Thus, the combined pool of mifepristone, as well as that of the metabolites, seems responsible for the biological actions of mifepristone. Combination therapy with mifepristone and low dose prostaglandin is currently in clinical use for termination of early pregnancy in China, France, Sweden and the UK. The combined regimen is well tolerated and highly efficacious with a 95% rate of complete pregnancy terminations. Recent clinical studies on pregnancy termination have focused on dose optimisation of mifepristone and evaluation of the orally active prostaglandin derivative misoprostol. In addition, several other indications for the clinical use of mifepristone, such as induction of labour, contraception, as well as treatment of various hormone dependent disorders, are emerging. The major obstacles currently inhibiting further evaluation and distribution of mifepristone are political rather than clinical. However, it is hoped that the eventual introduction of new antiprogesterone molecules by several manufacturers will enhance the availability of this important class of new drugs.

Medical abortion.

PIP: In 1996, an application was submitted to the US Food and Drug Administration for the use of mifepristone (RU-486) plus the prostaglandin misoprostol in medical abortion. Over 100,000 women in more than 20 countries have received this regimen, which results in pregnancy termination in 92.7-99.0% of treated women. This article presents state-of-the-art information on medical abortion. Reviewed are its pharmacokinetics and metabolism, mechanism of action, and history of use. The article outlines a standard protocol that includes RU-486 administration at the first visit (day 1), misoprostol administration at the second visit (day 3), and post-treatment examination at the third visit (days 14-20) and suggests counseling guidelines. It discusses the contraindications and potential complications of abortifacient agents. Finally, the article compares the experience in the US and Europe of medical versus surgical abortion in terms of effectiveness, complications, and acceptability.^ieng

Mifepristone (RU486): a review.

OBJECTIVE: To review the literature concerning the mechanism of action and pharmacodynamics of mifepristone (RU486), potential new uses of RU486, and its current use not only as an abortifacient but also as therapy for endometriosis, leiomyoma, breast cancer, and meningioma. DATA IDENTIFICATION AND SELECTION: Studies that relate to RU486 were identified through a MEDLINE search. CONCLUSION(S): RU486 is an 11 beta-dimethyl-amino-phenyl derivative of norethindrone with a high affinity for P and glucocorticoid receptors. The receptor binding is not followed by transcription of P-dependent genes. Mifepristone effectively blocks P receptors in the placenta, resulting in the termination of pregnancy. In addition, it has been used in the treatment of leiomyomata, endometriosis, advanced breast cancer, and meningioma. It is a powerful tool to study the molecular action of P and in the future may be used as an estrogen-free contraceptive.

PIP: Through an online search of MEDLINE, the authors reviewed the literature on the development of mifepristone (RU-486); RU-486's mechanism of action, pharmacodynamics, and distribution; the physiologic action of RU-486; potential new uses for RU-486; and its current use as both an abortifacient and therapy for endometriosis, leiomyoma, breast cancer, and meningioma. RU-486 is an 11beta-dimethyl-amino-phenyl derivative of norethindrone with a high affinity for P and glucocorticoid receptors. Receptor binding is not followed by the transcription of P-dependent genes. RU-486 effectively blocks P receptors in the placenta, resulting in the termination of pregnancy. It has also been used to treat leiomyomata, endometriosis, advanced breast cancer, and meningioma. The following therapeutic uses of RU-486 are discussed: the termination of early pregnancy, treatment with RU-486 in combination with prostaglandins, the termination of second-trimester pregnancy, cervical ripening, labor induction, postcoital contraception, uterine leiomyomata, endometriosis, breast cancer, and meningioma.

Pharmacokinetics of mifepristone after low oral doses.

Relatively low doses of the antiprogestin mifepristone (RU 486) have recently proven to be efficient for a variety of possible clinical uses of the drug. However, the pharmacokinetics after low single oral doses have not been characterized. We evaluated the pharmacokinetics of mifepristone following single ingestion of 2 and 25 mg in five women as well as repeated ingestion of 8 mg in two women. Maximal serum concentrations were reached rapidly (within 0.5-2 h) with all doses used. Serum mifepristone concentrations were proportional to the oral doses taken. The mean (+/- SD) areas under the concentration curves (AUCs) (0-24 h) were 1134 (+/- 144), 4846 (+/- 64), and 17,015 (+/- 4,421) h x ng/mL following 2, 8, and 25 mg doses, respectively. No cumulative increases in serum concentrations were detected with prolonged daily administration of 8 mg of mifepristone. The study subjects appeared to vary in their ability to metabolize mifepristone, as two different half-lives (t1/2) emerged after both 2 and 25 mg single doses (24.2 +/- 0.6 [SD] h for three subjects; and 44.4 +/- 1.8 [SD] h for two subjects). We conclude that within the dose range of 2-25 mg/day, the pharmacokinetics of mifepristone are linear, unlike those seen following ingestion of higher daily doses. Keeping in mind previously published data on the biological effects of low dose mifepristone administration, these data infer that certain effects of the drug, such as inhibition of ovulation, might be achieved at serum concentrations of approximately 100 ng/mL.

PIP: At the outpatient clinic of Lohja District Hospital in Lohja, Finland, clinical researchers examined the pharmacokinetics of mifepristone in 5 healthy women, 29-37 years old, receiving a single dose of 2 mg mifepristone and of 25 mg mifepristone and in 2 other women receiving 8 mg mifepristone each day for 30 days. Regardless of the dose, serum concentrations of mifepristone peaked within 1.2-1.4 hours. These concentrations were proportional to the oral doses: 104-227 ng/ml after 2 mg dose; 474-561 ng/ml after 8 mg dose; and 1285-4851 ng/ml after 25 mg dose. The areas under the concentration curves (0-24 hours) were also proportional to the oral doses: 1134.4, 4846, and 17,015.2, respectively. Daily doses of 8 mg mifepristone over 30 days did not effect cumulative increases in serum concentrations. The women taking the 2 mg and 25 mg single oral doses exhibited different half-lives (24.2 [3 women] vs. 44.4 [2 women] hours; p = 0.001), suggesting that they varied in their ability to metabolize mifepristone. These findings show that, at daily ingestion of 2-25 mg mifepristone, the pharmacokinetics of mifepristone are linear. Based on these findings, the authors think that inhibition of ovulation might be achieved at serum concentrations of about 100 ng/ml.

Pharmacokinetics of the antiprogesterone RU 486 in women during multiple dose administration.

Serum levels of RU 486 were measured by high performance liquid chromatography (HPLC) following oral intake of 12.5, 25, 50 and 100 mg twice daily (b.i.d.) for 4 days, 50 mg b.i.d. for 7 days, as well as a single dose of 200 mg of RU 486. The pharmacokinetics of RU 486 were not linear: when the daily dose of RU 486 was 100 mg or more, the serum levels were similar. The pharmacokinetic behaviour of RU 486 during the treatment period was similar between the study subjects, whereas the elimination phase pharmacokinetics showed wide individual variation. Also the mean elimination phase half-lifes (t 12) of RU 486 varied from 25.5 to 47.8 h in the groups of different regimen, yet the variation between different groups was not statistically significant. The areas under the concentration curves (AUC) were calculated. In the multiple dose study (mds) the AUC0----12h:s decreased when the administered dose of RU 486 was increased. The AUC0----12h seen after administration of 100 mg b.i.d. x 4d. (mean +/- SEM = 0.43 +/- 0.04 mumol/l x h/mg) was significantly (P less than 0.05) lower than the AUC0----12h:s obtained with administration of 12.5 mg b.i.d. x 4d. (1.49 +/- 0.37 mumol/l x h/mg), 25 mg b.i.d. x 4d. (1.09 +/- 0.15 mumol/l x h/mg), and 50 mg b.i.d. x 7d. (0.72 +/- 0.11 mumol/l x h/mg). The AUC0----infinity obtained by administration of a single dose of 200 mg of RU 486 (sds) was 0.67 +/- 0.21 mumol/l x h/mg. It is concluded that if multiple dose administration of RU 486 is preferred, daily administration of relatively small doses of RU 486 over several days seem to be advantageous.

Anti-progesterones: background and clinical physiology.

The development of anti-progesterones has provided a probe to examine the role of progesterone both in the normal cycle and in pregnancy. The most widely used of these agents, mifepristone, appears to act both directly at the endometrial progesterone receptor, and centrally by reducing circulating gonadotrophin concentrations. In addition, ovarian steroidogenesis may be modified. The clinical application of these agents for the interruption of pregnancy will be considered in the following chapters.