11β-hydroxylase; CYP450; Autophagy

HepG2 autophagy is overactivated by Metyrapone (100 μM; 2 hours), and severe endoplasmic reticulum (ER) early cell labeling activation is delayed [5].

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The binding of Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone) by Pseudomonas putida cytochrome P-450 is described. The absolute absorption spectrum of the Metyrapone-cytochrome P-450 complex in the ferric form has absorption maxima at 421 and 536 nm. In the ferrous form, this complex has absorption maxima at 442, 539, and 566 nm. The equilibrium constant for the binding of metyrapone by oxidized cytochrome P-450 is 2.3×108m−1 and the binding is competitive with the substrate camphor. Metyrapone inhibits the uptake of oxygen by the coupled monooxygenase system probably by competing with camphor for the camphor-binding site on oxidized cytochrome P-450. The results presented indicate that the camphor-binding site is close to the oxygen-activating site on cytochrome P-450.[4]

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Metyrapone is an autophagy activator, since it is shown to increase the efficiency of autophagic process via downregulation of mTOR pathway. The pretreatment of cells with Metyrapone before the addition of TM delayed the activation of apoptosis by more than 1 hr (Figures 5(c), 5(f) and S8(C)). Similar effects were observed by using TG or DTT (data not shown). These data show that autophagy has a crucial role in determining the activation threshold of apoptosis under ER stress. Its activation can shift the activation threshold of apoptosis to higher stress levels while its inhibition shifts it to lower stress levels [5].

Metyrapone (25 or 50 mg/kg; subcutaneous injection, single dose) enhances open-arm activity at low doses, greatly inhibits severe symptoms at high doses, and decreases the rise in adrenocorticosterone levels that is induced [1].

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Different levels of circulating corticosterone are considered to produce different emotional states and effects on learning and memory. The purpose of the present study was to use different doses of the 11-beta-hydroxylase inhibitor Metyrapone to produce dose-dependent inhibition of the synthesis of corticosterone and examine the consequences of that on several cognitive and emotional parameters. Systemic (SC) injections of Metyrapone (25 or 50 mg/kg) dose-dependently suppressed increases in plasma concentrations of corticosterone induced by spatial training in a water maze, but did not affect plasma corticosterone levels in non-stressed rats. Treatment with the higher and lower dose of metyrapone also differentially affected behavioral measures of emotion and memory. Administration of 50 mg/kg, but not 25 mg/kg, of metyrapone impaired acquisition performance in the spatial water maze task. Both doses of metyrapone impaired retention. The impairment in retention was attenuated by dexamethasone (0.3 mg/kg) given systemically immediately after training, but not by corticosterone (0.3 mg/kg). During the exposure to a conditioned stressor of inescapable footshock, the higher, but not the lower dose of metyrapone attenuated fear-induced immobility. In contrast, the lower, but not the higher dose attenuated the anxiety state in an elevated plus-maze in a novel environment immediately after exposure to the conditioned stressor. It is suggested that emotion, learning, and memory are differentially affected by the different doses of metyrapone due to interference with different types of adrenal steroid receptors and consequent induction of various corticosterone receptor states.[1]

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Using intention-to-treat analysis, we found that a higher proportion of patients receiving Metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects.
Conclusions: Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.[2]

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Results: A total of 164/195 received Metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible.
Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS [3].

Cell Culture and Maintenance [5]
As model system, human liver carcinoma (HepG2) and human embryonic kidney (HEK293) cell lines were used. It was maintained in DMEM (Life Technologies, 41965039) medium supplemented with 10% fetal bovine serum and 1% antibiotics/antimycotics. Culture dishes and cell treatment plates were kept in a humidified incubator at 37°C in 95% air and 5% CO2.

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SDS-PAGE and Western Blot Analysis [5]
Cells were harvested and lysed with 20 mM Tris, 135 mM NaCl, 10% glycerol, 1% NP40, and pH 6.8. Protein content of cell lysates was measured using Pierce BCA Protein Assay. During each procedure equal amounts of protein were used. SDS-PAGE was done by using Hoefer miniVE. Proteins were transferred onto Millipore 0.45 μM PVDF membrane. Immunoblotting was performed using TBS Tween (0.1%), containing 5% nonfat dry milk for blocking membrane and for antibody solutions. Loading was controlled by developing membranes for GAPDH or dyed with Ponceau S in each experiment. The following antibodies were applied: anti-LC3B, anti-caspase-3, anti-PARP, anti-p62, and anti-GAPDH and HRP conjugated secondary antibodies.

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Cell Viability Assays [5]
Cell viability was detected using CellTiter-Blue assay. Cells were grown and treated on 96-well plates and were incubated with resazurin for 2 h at 37°C. Absorbance was measured at 620 nm and expressed in arbitrary unit, being proportional to cell toxicity. For each of these experiments at least three parallel measurements were carried out.

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Annexin Staining [5]
Apoptotic and necrotic cells were detected by using fluorescence microscopy and Annexin-V-FLUOS staining kit. Cells were grown and treated on 96-well plates and were treated with the kit according to the manufacturer's instructions. Cells with green fluorescence were considered as apoptotic, while those with red or both red and green (orange) fluorescence were considered as necrotic. In each experiment a minimum of 1000 cells was counted.

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats (n=179; 270-300g)[1]
Doses: 25 or 50mg/kg (volume is 2.0mL/kg)
Route of Administration: SC, single dose
Experimental Results: dose- ]. Dependently diminished the stress-induced increase in plasma corticosterone levels in the water maze test; high dose Dramatically impaired acquisition performance in the water maze and diminished fear-induced immobility; lower dose increased Open arm activities.

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Drug Treatment [1]
Two doses of the 11-beta-hydroxylase inhibitor Metyrapone [2-methyl-l,2-di-3-pyridyl-1- propanone (Sigma)] 25 or 50 mg/kg (in a volume of 2.0 ml/kg) were injected SC 90 min before the exposure of the animals to the test situation. The drug was dissolved in polyethylene glycol and diluted with a 0.9% saline solution to reach the appropriate concentration. The final concentration of polyethylene glycol was 40%. The vehicle control contained the same polyethylene glycol concentration. Each animal received only one injection of Metyrapone or the vehicle control solution. Corticosterone or the synthetic glucocorticoid dexamethasone was administered at a dose of 0.3 mg/kg SC (in a volume of 2.0 ml/kg) immediately after completion of five training trials in a water maze task (see below). These drugs were dissolved in 100% ethanol and subsequently diluted in 0.9% saline to reach the appropriate concentration. The final concentration of ethanol was 2%.

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Water Maze Task [1]
The water maze was a circular galvanized steel tank 1.83 m in diameter and 0.58 m in height. The tank was filled with water (27°C) to a depth of 20 cm. The maze was located in a room containing several extramaze cues. Four starting positions were equally spaced around the perimeter of the pool. A Perspex platform (20 x 25 cm) was placed 25 cm away from the edge of the pool. The platform was submerged 2.5 cm below the water surface. On the training day, each rat received an SC injection of either vehicle or Metyrapone (25 or 50 mg/kg) 90 min before training. Before the first training trial the rat was directly placed on the submerged platform for 30 s. On each of five trials (i.e. swims), the rat was placed into the tank randomly at one of the four designated starting points, facing the wall, and allowed to escape onto the submerged platform. The platform was located in a fixed position during the entire procedure. If an animal did not escape within 60 s starting from the release into the tank, it was manually guided to the platform. Latency to mount the platform was recorded on all trials. After mounting the platform the animal was allowed to stay there for 20 s, and was subsequently placed into a holding cage for 30 s until the start of the next trial. Immediately after completion of these five trials, the rats received an SC injection of either vehicle or 0.3 mg/kg corticosterone or dexamethasone. Retention was tested 48 h after training. Three retention trials were given, with the platform in the same location as during the training trials. The latency to escape on each of these three trials was recorded. The average latency on these three trials was used as the index of retention.

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Fear-induced Immobility [1]
The experiment was designed on the basis of previous evidence (Roozendaal et al., 1990) indicating that rats display immobility when tested in an apparatus where they previously received a footshock. The rats were trained in a step-through inhibitory avoidance apparatus (McGaugh et al., 1988) located in a sound-attenuated room. The apparatus consisted of a trough-shaped alley (91 cm long, 15 cm deep, 20 cm wide at the top, 6.4 cm wide at the floor) divided into two compartments separated by a sliding door that opened by retracting into the floor. The starting compartment (31 cm long) was illuminated and the shock compartment (60 cm long) was dark. On the training day, the rat was placed in the starting compartment of the apparatus with an open door. As the rat stepped into the dark compartment, the sliding door was closed and an inescapable footshock (0.45 mA for 3 s) was given immediately in half of the animals (stress group). The rat was removed from the dark alley 30 s after termination of the footshock. In the remaining animals, no footshock was administered and the rat was retained in the dark compartment for 30 s (control group) and then returned to its home cage. Forty-eight hours later, each animal received an SC injection of either vehicle or Metyrapone (25 or 50 mg/kg) 90 min before testing. The animal was placed directly in the dark compartment (with closed sliding door) in which no further footshock was given. The effect of drug treatment on the relative time spent on immobility (i.e. when the animal was completely motionless) was measured for a period of 5 min.

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Medication [2]
The 63 participants who met the inclusion criteria were randomly assignedto the treatment groups. The pharmacological reason for the use of serotonergiccompounds is based on the presumed hippocampal effects of Metyrapone on 5HT-1Areceptors. The clinical rationale for the use of these compounds is basedon activating properties of fluvoxamine and sedative effects of nefazodone,allowing inclusion of inhibited as well as agitated patients. The respectiveantidepressant was selected according to clinical symptomatology.
Following baseline assessments, subjects entered a 3-week, double-blindtreatment period with either Metyrapone (250 mg given orally 4 times a day)or placebo (4 times a day) at 8 AM, 12 PM, 6 PM, and 10 PM, in addition to a standard antidepressanttreatment with nefazodone or fluvoxamine. The dose range for fluvoxamine was150 to 200 mg/d and for nefazodone 300 to 400 mg/d after 1 week of treatment.
The medication with Metyrapone or placebo and each of the serotonergicantidepressants was started simultaneously on day 1 of the study. After day21, patients continued to take the antidepressant, but metyrapone or placebomedication was stopped. The study ended after 5 weeks.
Both serotonergic antidepressants were given as commercially availableoriginal medication. Metyrapone was capsuled, and identical placebo capsuleswere produced. Allocation codes were provided in sealed envelopes for eachpatient at the pharmacy of University Hospital Hamburg, where formulationand blinding were conducted. The randomization was organized by a computer-generatedlist using the PLAN procedure from the SAS/STAT software (SAS Institute Inc,Cary, NC). The concomitant use of lorazepam was allowed for a maximum of 8days from day 0 to day 7 of the 35-day treatment period.

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A multicenter, retrospective study was performed across 13 University hospital centers in England and Wales, members of the United Kingdom Endocrine Neoplasia Collaboration. Patients treated with Metyrapone were identified through pharmacy records and electronic databases. Patients with a diagnosis of CS and treated with metyrapone between 1997 and 2013 were included.
The same proforma was used in all centers to record anonymized data. Data were gathered from case records and electronic record systems. Baseline, demographic and safety data, the indication for treatment and dose of Metyrapone therapy, any therapeutic intervention and any recorded adverse events were documented. Monitoring tests included early morning (9 am) serum cortisol, 24-hour urinary free cortisol (UFC), serum potassium, plasma ACTH, and serum cortisol “day-curves” (CDCs). In CDCs multiple samples for serum cortisol are collected across the day with the mean calculated (11). The majority (91%) of CDCs consisted of 4 or 5 serum cortisol samples (minimum 3, maximum 8, median 4). All tests performed during the monitoring period were collected and analyzed. All centers used immunoassay-based cortisol assays.
Patients were treated either with a dose titration regimen, ie, Metyrapone dose was up-titrated according to response to achieve a biochemical target for cortisol, or a block-and-replace regimen, where the dose of metyrapone was quickly up-titrated to achieve blockade of cortisol synthesis and a replacement dose of glucocorticoid was added to provide background physiological levels.[3]

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Absorption, Distribution and Excretion
Absorbed rapidly and well when administered orally. Peak plasma concentrations are usually reached 1 hour after administration.
After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.
GASTROINTESTINAL ABSORPTION OF METYRAPONE IS VARIABLE. FOLLOWING ORAL ADMIN OF 750 MG OF METYRAPONE EVERY 4 HR TO NORMAL PT, PEAK PLASMA LEVELS OF ABOUT 1.2 UG M/L...REACHED AFTER THIRD DOSE...0.4 UG/ML...PRESENT IMMEDIATELY AFTER SIXTH DOSE.
...PLASMA LEVELS OF METYRAPONE...IN RATS WERE SHOWN TO EXHIBIT A CIRCADIAN PATTERN WHEN ANIMALS WERE KEPT IN ALTERNATING 12-HR LIGHT-12 HR DARK REGIMEN. HALF-LIFE...OBSERVED @ 10:00 PM WAS APPROX 2.5 TIMES LONGER THAN THAT OBSERVED @ 10:00 AM...
...WITHIN 2 DAYS FOLLOWING ORAL ADMIN OF 750 MG...EVERY 4 HR FOR 6 DOSES, APPROX 0.5%...IS EXCRETED IN URINE UNCHANGED, 3% IS EXCRETED AS REDUCED METABOLITE, & 37% AS GLUCURONIDE CONJUGATES OF METYRAPONE & ITS METABOLITES.

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Metabolism / Metabolites
Hepatic. The major biotransformation is reduction of the ketone to metyrapol, an active alcohol metabolite. Metyrapone and metyrapol are both conjugated with glucuronide.
/METYRAPONE IS METABOLIZED BY/ ONE ENZYME, PRESENT IN MICROSOMAL FRACTION OF RAT LIVER, IS NADPH-DEPENDENT & IS ACTIVE UNDER AEROBIC CONDITIONS, REDUCING COMPD TO 2-METHYL-1,2-BIS-(3-PYRIDYL)PROPAN-1-OL...SECOND ENZYME...HAS NOT BEEN IDENTIFIED...

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Biological Half-Life
1.9 ±0.7 hours.
METYRAPONE HAS PLASMA HALF-LIFE OF ABOUT 20-26 MIN.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Evidence from two patients indicate that amounts of Metyrapone and its active metabolite in breastmilk are very small and unlikely to adversely affect a breastfed infant. Exposure of the infant can be markedly decreased by avoiding nursing for 2 to 2.5 hours after each dose.
◉ Effects in Breastfed Infants
A woman was taking metyrapone 250 mg 3 times daily, as well as bisoprolol 10 mg and captopril 12.5 mg twice a day postpartum. She breastfed her preterm infant about 50% milk and 50% formula. At 5 weeks postpartum, infant blood was collected. ACTH was 160 ng/L, cortisol was 98 nmol/L, 11-deoxycortisol was 2 nmol/L, sodium was 133 mmol/L, and potassium was 4.8 mmol/L. All values were within normal limits and his pediatric team found his growth and development to be appropriate.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date. Women taking metyrapone chronically for suppression of hypercorticism associated with Cushing's syndrome may have other hormonal abnormalities that might interfere with lactation.

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Interactions
SUBNORMAL RESPONSE TO METYRAPONE MAY...OCCUR IN PT RECEIVING ESTROGENS, PROGESTOGENS, CORTICOSTEROIDS, PHENOTHIAZINES, CHLORDIAZEPOXIDE, CHLORPROMAZINE, AMITRIPTYLINE, PHENOBARBITAL, OR METHYSERGIDE. ESTROGEN-PROGESTOGEN ORAL CONTRACEPTIVES...REPORTED TO BOTH REDUCE & ELEVATE RESPONSE TO METYRAPONE.
PRETREATMENT WITH METYRAPONE PROVOKED HYPERSECRETION OF FSH FOLLOWING SINGLE INJECTION OF LRH.
METYRAPONE REDUCED METABOLITE FORMATION BY 3-HYDROXYLATION & N-1-DEMETHYLATION, BUT HAD NO EFFECT ON C-4'-HYDROXYLATION OF DIAZEPAM.
POTENTIATION OF HYPOTHALAMIC-PITUITARY-ADRENAL RESPONSE TO METYRAPONE BY L-DOPA IN ACROMEGALIC PATIENT.

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Safety and tolerability [2]
The Metyrapone treatment was well tolerated, and no serious adverseeffects occurred. Minor adverse effects had a low incidence (Table 5) and were predominantly reported by women (mean ± SEMadverse events reported: women, 3.32 ± 0.47; men, 2.55 ± 0.40).Only nausea and headaches were reported significantly more often during metyraponetreatment compared with placebo (Fisher exact P = .037and P = .048, respectively). Adverse effectswere mainly due to the serotonergic antidepressant treatment, especially inthe first 2 weeks. Patients receiving fluvoxamine reported more nausea andrestlessness, while patients taking nefazodone complained more frequentlyof a dry mouth. We did not observe any alterations in general clinical chemistryparameters.

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Safety considerations [3]
Side effects were noted in 48/195 patients (25%): 88% were managed as outpatients, whereas 12% (7/57 events) required either admission for evaluation or prolongation of a current admission. The rate of adverse events in patients on therapy for more than 6 months was 11% (4/38 patients). There were no pregnant women and no deaths recorded due to an adverse event. The average dose of Metyrapone at the time of an adverse event was 1600 mg. Gastrointestinal (GI) upset (23%) and hypoadrenalism (7%, symptoms of dizziness, hypotension, with biochemical confirmation) were the most common side effects. Most adverse events (39/56) occurred within 15 days of initiation of metyrapone or after a dose increase. GI upset and dizziness were the main reasons for discontinuing treatment. Patients with confirmed hypoadrenalism were managed either by addition of glucocorticoid (regimen change to a block-and-replace) or temporary cover with glucocorticoid and simultaneous reduction of metyrapone dose. In 15% of cases, the metyrapone dose was reduced. In 12 cases (23%), metyrapone was withdrawn temporarily or permanently, with 11/12 showing full resolution, and in 1, symptoms continued but became less severe, muscle aches at presentation worsened during metyrapone therapy but returned to pretreatment levels after drug withdrawal. Symptoms of hyperandrogenism were not frequent; hirsutism was not reported, and there was only 1 case of worsening acne during treatment. Similarly, edema was only reported in 1 case, but the causative drug was thought to be a calcium channel blocker. Hypoglycemia was reported in 3 patients on diabetic medications and was associated with improvement of hypercortisolism. Potassium levels were monitored and actively treated at presentation and during therapy. In 138 patients on metyrapone monotherapy, with no other treatment interventions for their CS, mean potassium levels increased from 3.68 to 3.90 nmol/L (P = .003) during treatment (Figure 3).

[1]. Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory. Psychoneuroendocrinology. 1996 Nov;21(8):681-93.

[2]. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry. 2004 Dec;61(12):1235-44.

[3]. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab. 2015 Nov;100(11):4146-54.

[4]. Peterson JA, Ullrich V, Hildebrandt AG. Methyrapone interaction with Pseudomonas putida cytochrome P-405. Arch Biochem Biophys. 1971 Aug;145(2):531-42.

[5]. A Comprehensive Systems Biological Study of Autophagy-Apoptosis Crosstalk during Endoplasmic Reticulum Stress. Biomed Res Int. 2015;2015:319589.

Metyrapone is an aromatic ketone that is 3,3-dimethylbutan-2-one in which the methyl groups at positions 1 and 4 are replaced by pyridin-3-yl groups. A steroid 11beta-monooxygenase (EC 1.14.15.4) inhibitor, it is used in the diagnosis of adrenal insufficiency. It has a role as a diagnostic agent, an antimetabolite and an EC 1.14.15.4 (steroid 11beta-monooxygenase) inhibitor.
An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of cushing syndrome.
Metyrapone is an Adrenal Steroid Synthesis Inhibitor. The mechanism of action of metyrapone is as an Adrenal Steroid Synthesis Inhibitor.
Metyrapone is a pyridine derivative and a glucocorticoid synthesis inhibitor. Metyrapone inhibits 11-beta-hydroxylase, thereby inhibiting synthesis of cortisol from 11-deoxycortisol and corticosterone from desoxycorticosterone in the adrenal gland. Removal of the negative feedback mechanism exerted by cortisol results in increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland. In turn, continuing stimulation of adrenal gland by ACTH results in accumulation of corticoid precursors, 11-desoxycortisol and desoxycorticosterone. These metabolites are excreted in urine that maybe used as indicators for pituitary responsiveness.
An inhibitor of the enzyme STEROID 11-BETA-MONOOXYGENASE. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of CUSHING SYNDROME.
See also: Metyrapone Tartrate (has salt form).

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Drug Indication
Used as a diagnostic drug for testing hypothalamic-pituitary ACTH function. Occasionally used in Cushing's syndrome.

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Mechanism of Action
The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-ß-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.
METYRAPONE REDUCES CORTISOL PRODUCTION BY INHIBITION OF 11BETA-HYDROXYLATION REACTION. BIOSYNTHETIC PROCESS IS TERMINATED @ 11DESOXYCORTISOL... IN NORMAL PERSON...INCR IN ACTH RELEASE FOLLOWS, & SECRETION OF 11DESOXYCORTISOL...ACCELERATED.
ORAL ADMIN OF 250 MG/SQ M BODY SURFACE INCR PLASMA CONCN OF GLUCOSE & GROWTH HORMONE IN CHILDREN.
@ LOW DOSES PGE2 & PGF2ALPHA RELEASE WERE STIMULATED. @ HIGHER DOSES PGF2ALPHA RELEASE WAS INHIBITED.

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Therapeutic Uses
METYRAPONE IS USED TO TEST ABILITY OF PITUITARY TO RESPOND TO DECR CONCN OF PLASMA CORTISOL. ADMIN...TO PT WITH DISEASE OF HYPOTHALAMICO-PITUITARY COMPLEX.../IS/ NOT FOLLOWED BY INCR RENAL EXCRETION OF "17-HYDROXYCORTICOIDS."
.../METYRAPONE HAS/ BEEN USED WITH SPIRONOLACTONE & PREDNISONE TO RELIEVE SEVERE EDEMA, BUT...HAS BEEN REPLACED BY MORE POTENT DIURETICS. .../ALSO/ USED INVESTIGATIONALLY TO LOWER PLASMA CHOLESTEROL LEVELS IN PT WITH FAMILIAL HYPERCHOLESTEROLEMIA TYPE II, BUT WELL-CONTROLLED CLINICAL STUDIES...NOT YET AVAILABLE.
METYRAPONE MAY BE USED TO CONFIRM DEXAMETHASONE SUPPRESSION TEST RESULTS IN DIFFERENTIAL DIAGNOSIS OF ADRENAL HYPERPLASIA & ADRENAL ADENOMA...RESULTS OF THIS TEST MUST BE INTERPRETED CAUTIOUSLY.
METYRAPONE HAS BEEN USED EXPTL TO TREAT HYPERCORTISOLISM THAT RESULTS FROM ADRENAL NEOPLASMS THAT FUNCTION AUTONOMOUSLY & FROM ECTOPIC ACTH PRODUCTION BY TUMORS. IT IS NOT SUITABLE FOR CORRECTING EXCESSIVE CORTISOL SECRETION OF CUSHING'S SYNDROME CAUSED BY HYPERSECRETION OF PITUITARY ACTH.
...ADMIN OF METYRAPONE CAN BE USED AS TEST FOR NORMAL HYPOTHALAMICO-PITUITARY FUNCTION ONLY IF ADRENAL GLANDS ARE CAPABLE OF RESPONDING TO ACTH...

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Drug Warnings
IN HIGH DOSES, METYRAPONE MAY INHIBIT 18- & 19-HYDROXYLASE ENZYMES, THUS INHIBITING SYNTHESIS OF OTHER STEROIDS, INCL ESTROGENS. ...DRUG MAY ALSO DECR PLASMA HALF-LIFE OF CORTISOL, INCR GROWTH HORMONE RELEASE, & INDUCE HYPERGLYCEMIA.
...DRUG MAY INDUCE ACUTE ADRENAL INSUFFICIENCY IN PT WITH REDUCED ADRENAL SECRETORY CAPACITY. METYRAPONE ALSO INHIBITS SYNTHESIS OF ALDOSTERONE... HOWEVER.../IT/ DOES NOT TYPICALLY CAUSE DEFICIENCY IN MINERALOCORTICOIDS, WITH CONSEQUENT LOSS OF SODIUM & RETENTION OF POTASSIUM...
OCCASIONALLY, ARTERIAL BLOOD PRESSURE MAY FALL & MODERATE INCR IN PULSE RATE MAY INSUE. ...SHOULD NOT BE USED IN PT WITH ADRENOCORTICAL INSUFFICIENCY...SAFE USE OF DRUG IN PREGNANCY HAS NOT BEEN ESTABLISHED.
ABILITY OF ADRENAL TO RESPOND TO ACTH SHOULD BE DEMONSTRATED BEFORE METYRAPONE IS EMPLOYED...
For more Drug Warnings (Complete) data for METYRAPONE (8 total), please visit the HSDB record page.

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Pharmacodynamics
Metopirone is an inhibitor of endogenous adrenal corticosteroid synthesis.

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In sum, the findings of the present studies clearly indicated that lower and higher doses of metyrapone differentially affected learning, memory and emotional expressions. The findings are consistent with the assumption that metyrapone has a dose-dependent effect on 692 B. Roozendaal et al. MR- and GR-mediated processes. This suggestion is also supported by the effects induced by posttraining injections of corticosterone and dexamethasone on retention of the water maze task. MRs and GRs are involved in different aspects of anxiety and fear-motivated behaviors. MRs are involved in the expression of fear in situations where the animal reacts with freezing behavior. GRs seem to be more involved in mechanisms underlying the generalization of anxiety. In the water maze, MRs have been shown to be involved in developing a behavioral strategy to search for the platform, whereas GRs are involved in the regulation of memory consolidation. [1]

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This study carries the limitations imposed by its retrospective design. Furthermore, there is currently no standardized monitoring and dosing regimen for patients on metyrapone therapy. The monitoring of hypercortisolemia in patients with CS on medical treatment is important to ensure that patients are treated with the correct dose and that hypoadrenalism, if present, is recognized early; measurement of serum cortisol allows this. Even though the study was conducted in University centers with significant expertise in the management of CS, the choice of biochemical monitoring test and frequency of monitoring varied. This has affected the uniformity of the data presented. During the period of the study, the common clinical practice was to aim for a 9 am cortisol bellow the ULN for the assay used or less than 600 nmol/L. Any results above these levels would prompt up-titration of the dose or addition of a second agent. Therefore, we have reported these cut-offs as the criteria for normalization of hypercortisolemia. More stringent 9 am serum cortisol levels to define control have been proposed recently, with suggested values below 331 nmol/L (12 µg/dL). It is not possible to know whether clinicians would have up-titrated the dose of metyrapone had this criterion been used, and therefore, we can only speculate that the overall control when using this criterion might have been better if applied in practice. In conclusion, our data show that metyrapone is effective and safe in treating hypercortisolemia in patients with CS.[3]

C14H14N2O

226.2738

226.11

C, 74.31; H, 6.24; N, 12.38; O, 7.07

54-36-4

Metyrapone Tartrate;908-35-0

4174

White to yellow solid powder

1.1±0.1 g/cm3

384.4±22.0 °C at 760 mmHg

53-56ºC

189.3±28.8 °C

0.0±0.9 mmHg at 25°C

1.565

1.19

0

3

3

17

275

0

CC(C)(C1=CN=CC=C1)C(=O)C2=CN=CC=C2

FJLBFSROUSIWMA-UHFFFAOYSA-N

InChI=1S/C14H14N2O/c1-14(2,12-6-4-8-16-10-12)13(17)11-5-3-7-15-9-11/h3-10H,1-2H3

2-methyl-1,2-dipyridin-3-ylpropan-1-one

metyrapone; 54-36-4; 2-Methyl-1,2-di-3-pyridyl-1-propanone; Methopyrapone; Metopiron; Methapyrapone; Methopirapone; Methopyrinine;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~441.95 mM)
H2O : ≥ 38 mg/mL (~167.94 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (441.95 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)