ミフェプリストン

ミフェプリストンは、プロゲステロン受容体とグルココルチコイド受容体の両方のアンタゴニストとして作用します。プロゲステロン受容体に結合することで、ホルモンがその効果を発揮することを阻止し、子宮内膜の分解と妊娠の中絶を引き起こします。 高用量では、ミフェプリストンはグルココルチコイド受容体もブロックし、クッシング症候群などの治療に役立ちます .

Mifepristone is a synthetic steroid compound with antiprogestational and antiglucocorticoid properties . While widely known as a medication for terminating early pregnancies, its applications extend to treating various other health conditions . Mifepristone functions as a progesterone receptor antagonist, blocking the effects of progesterone, a hormone essential for maintaining pregnancy . This mechanism allows mifepristone to affect hormonal activity, leading to diverse medical applications .

Scientific Research Applications

Mifepristone has several applications beyond abortion care, including the treatment of Cushing’s syndrome, uterine fibroids, hormone-sensitive cancers, and potentially PTSD .

Cushing's Syndrome
Mifepristone is approved by the FDA for treating Cushing’s syndrome, a condition characterized by elevated cortisol levels . By blocking cortisol receptors, mifepristone helps manage blood sugar levels and alleviate symptoms like weight gain and fatigue .

Uterine Fibroids
Mifepristone can shrink uterine fibroids and relieve symptoms such as heavy menstrual bleeding and pelvic pain . Its hormone-blocking action provides a non-invasive alternative to surgery for managing fibroids .

Emergency Contraception
Mifepristone may also be used as an emergency contraceptive by preventing implantation in the early stages of pregnancy .

Hormone-Sensitive Cancers
Mifepristone is being studied as a potential treatment for hormone-sensitive cancers like breast and ovarian cancer by blocking progesterone’s role in tumor growth .

Post-Traumatic Stress Disorder (PTSD)
Mifepristone is also being researched for the treatment of PTSD . A study investigated the efficacy of mifepristone in treatment-resistant PTSD patients. Two out of three patients experienced a significant reduction in PTSD symptom severity after mifepristone treatment and no longer met the diagnostic criteria for PTSD .

Pharmacokinetics

Mifepristone is administered orally and is rapidly absorbed . It has a bioavailability of 69% following a 20 mg oral dose . The compound is highly bound (98%) to plasma proteins, including albumin and a 1-acid glycoprotein .

Efficacy and Safety

Mifepristone has been extensively studied for its safety and efficacy . A study involving 13,373 women reported that a regimen of 200 mg mifepristone orally, followed by 800 mcg misoprostol buccally 24–48 hours later, was safe and effective through 63 days of gestation . The overall efficacy of this regimen was 97.7% .

Data Table

Case Studies

PTSD Treatment
Three patients with PTSD, resistant to standard treatments, were prescribed mifepristone (600-1,200 mg/day) for one week . A baseline-controlled single-case design was used, including a 2-week baseline phase, a 1-week intervention phase (mifepristone), and a 2-week post-intervention phase . Self-reported PTSD symptom severity was assessed daily . Two of the three patients experienced a significant reduction in PTSD symptom severity after the intervention phase and no longer met the diagnostic criteria for PTSD . These positive results were maintained during long-term follow-up .

Biochemical Properties

Mifepristone acts as a competitive progesterone receptor antagonist . In the absence of progesterone, mifepristone acts as a partial agonist . It works by blocking the effects of progesterone, making both the cervix and uterine vessels dilate and causing uterine contraction . Mifepristone is also a glucocorticoid receptor antagonist .

Cellular Effects

Mifepristone has been shown to inhibit ovarian cancer cell proliferation in a dose- and time-dependent manner . It also induced fewer alveoli, enlarged alveolar lumina, and altered the levels of hormones such as estrogen, progesterone, prolactin, growth hormone, corticosterone, and oxytocin, as well as the mRNA expression of these hormonal receptors during pregnancy or early lactation .

Molecular Mechanism

Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses . It works by blocking the effects of progesterone, which is necessary for a pregnancy to continue . Mifepristone’s inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua .

Temporal Effects in Laboratory Settings

In a 24-week multicenter, open-label trial, mifepristone produced significant clinical and metabolic improvement in patients with Cushing’s syndrome with an acceptable risk-benefit profile during 6 months of treatment . Mifepristone treatment reduced cellular proliferation and viability of all UM cell lines studied in a concentration-dependent manner .

Dosage Effects in Animal Models

In animal models, mifepristone administration at the dose of 1.20 mg/kg body weight on pregnancy day 4 caused a significant reduction in milk production on lactation day 1, lactation day 2, and lactation day 3 . Mifepristone also induced an increase in the weight of epididymal, perirenal, and gluteofemoral adipose tissues .

Metabolic Pathways

Mifepristone is extensively metabolised by demethylation and hydroxylation, the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4 . The three most proximal metabolites, namely the monodemethylated, didemethylated, and hydroxylated metabolites of mifepristone, all retain considerable affinity toward the human progesterone and glucocorticoid receptors .

Transport and Distribution

The serum transport protein α1-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 .

Subcellular Localization

Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21 cip1 and p27 kip1 and reduced nuclear cdk2/cyclin E complex availability . This suggests that mifepristone may regulate mitochondrial function through the control of mitochondrial gene expression .

Synthetic Routes and Reaction Conditions: Mifepristone is synthesized through a multi-step process involving several key intermediates. The synthesis begins with the preparation of 11β-[4-(dimethylamino)phenyl]-17β-hydroxy-17α-(1-propynyl)estra-4,9-dien-3-one. This intermediate is then subjected to various chemical reactions, including hydroxylation and alkylation, to produce the final compound .

Industrial Production Methods: In industrial settings, mifepristone is produced using a wet granulation method. This involves mixing the active pharmaceutical ingredient with excipients such as starch and microcrystalline cellulose, followed by granulation with a water/alcohol mixture. The granules are then dried and compressed into tablets .

Types of Reactions: Mifepristone undergoes several types of chemical reactions, including:

Oxidation: Mifepristone can be oxidized to form various metabolites.

Reduction: Reduction reactions can modify the ketone group in mifepristone.

Substitution: Substitution reactions can occur at the dimethylamino group.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include potassium permanganate and chromium trioxide.

Reduction: Reducing agents such as sodium borohydride and lithium aluminum hydride are used.

Substitution: Reagents like alkyl halides and amines are employed for substitution reactions.

Major Products Formed: The major products formed from these reactions include various hydroxylated and demethylated metabolites, such as N-desmethyl-mifepristone and 22-hydroxy-mifepristone .

ミフェプリストンは、プロゲステロン受容体アンタゴニストとして知られる化合物群に属します。類似の化合物には、以下のようなものがあります。

レボノルゲストレル： 緊急避妊に使用されますが、アンタゴニストではなく、主にプロゲステロンとして作用します.

ユリプリスタルアセテート： 緊急避妊と子宮筋腫の治療に使用される、別のプロゲステロン受容体モジュレーターです.

アソプリスニル： 子宮内膜症や子宮筋腫の治療に用いられる、選択的プロゲステロン受容体モジュレーターです.

ミフェプリストンの独自性： ミフェプリストンは、プロゲステロンとグルココルチコイド受容体の両方のアンタゴニストとして作用するという独自の特徴を持つため、このクラスの他の化合物とは一線を画しています。 この二重の作用により、妊娠の終了からホルモン障害の管理まで、幅広い医療用途で非常に効果的です .

Mifepristone, a synthetic steroid compound, is primarily known for its role as a glucocorticoid receptor antagonist and a progesterone receptor antagonist. Its biological activity extends across various therapeutic areas, including reproductive health and mental health disorders. This article explores the compound's mechanisms of action, efficacy in clinical settings, and findings from recent studies.

Glucocorticoid Receptor Antagonism
Mifepristone acts as a competitive inhibitor of the glucocorticoid receptor (GR), which is crucial for mediating the effects of cortisol. By blocking this receptor, mifepristone can modulate the hypothalamic-pituitary-adrenal (HPA) axis, potentially lowering cortisol's physiological effects without reducing its production. This mechanism is particularly beneficial in treating conditions like Cushing's syndrome, where excess cortisol leads to various health issues .

Progesterone Receptor Antagonism
As a progesterone receptor antagonist, mifepristone inhibits the action of progesterone, which is vital in maintaining pregnancy. This action is leveraged in medical abortions up to 70 days gestation when used in combination with misoprostol . The anti-progestational effects are achieved through competitive binding at progesterone-receptor sites, leading to decidual breakdown and termination of pregnancy .

Case Studies and Trials

• Post-Traumatic Stress Disorder (PTSD)
  A study involving three treatment-resistant PTSD patients demonstrated that mifepristone significantly reduced PTSD symptom severity. Two out of three patients no longer met diagnostic criteria after one week of treatment with doses ranging from 600 to 1200 mg/day . This suggests mifepristone's potential as an adjunct therapy in PTSD management.
• Veteran Population Study
  A randomized clinical trial with 81 male veterans assessed the efficacy of mifepristone in treating PTSD symptoms over 12 weeks. The results indicated a 7% higher response rate in the mifepristone group compared to placebo, although this did not meet the predefined margin for clinical significance . Further exploratory analyses suggested potential benefits among subgroups without traumatic brain injury.

Summary of Findings from Recent Studies

Biological Effects Beyond Reproductive Health

Recent research has also explored mifepristone's effects on lifespan and metabolic processes. In Drosophila models, mifepristone was shown to increase lifespan significantly while altering gut microbiome composition and reducing metabolic activity associated with food intake . These findings suggest broader implications for mifepristone beyond its traditional uses.

Safety and Side Effects

While mifepristone is generally well-tolerated, some side effects include gastrointestinal disturbances and hormonal imbalances due to its antagonistic actions on progesterone and glucocorticoid receptors. A prospective study on pregnancies following first-trimester exposure to mifepristone reported a low rate of major congenital malformations (4.2%), comparable to general population rates . This provides reassurance regarding its safety profile when used appropriately.