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.\n

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\n\nDrug Treatment [1]
\nTwo 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%. \n

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\n\nWater Maze Task [1]
\nThe 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. \n

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\n\nFear-induced Immobility [1]
\nThe 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. \n

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\n\nMedication [2]
\nThe 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.\n
\nFollowing 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.\n
\nThe 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.\n
\nBoth 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.\n\n

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\n\nA 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.\n
\nThe 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.\n
\nPatients 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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\n\n

Absorption, Distribution and Excretion
Absorption after oral administration is rapid and good. Peak plasma concentrations are typically reached 1 hour after administration. Following administration of 4.5 g metheprone (750 mg every 4 hours), an average of 5.3% of the dose is excreted in the urine over 72 hours as metheprone (9.2% free, 90.8% glucuronide), and 38.5% as metheprone (8.1% free, 91.9% glucuronide). Gastrointestinal absorption of metheprone varies among individuals. After oral administration of 750 mg metheprone every 4 hours to normal PT, peak plasma concentrations are approximately 1.2 μg/L…reached after the third dose…0.4 μg/L…immediately after the sixth dose. …In rats, plasma concentrations of metheprone exhibit a diurnal rhythm when animals are under 12-hour light-12-hour dark conditions. Half-life… The half-life observed at 10:00 PM is approximately 2.5 times that observed at 10:00 AM… …After oral administration of 750 mg every 4 hours for a total of 6 doses, within 2 days, approximately 0.5% is excreted unchanged in the urine, 3% is excreted as reduced metabolites, and 37% is excreted as glucuronide conjugates of metheprone and its metabolites. Metabolism/Metabolites Hepatic metabolism. The main biotransformation is the reduction of the ketone to the active alcohol metabolite metheprone. Both metheprone and metheprone are conjugated with glucuronic acid.
/Metheprone is metabolized by an enzyme present in the microsomal fraction of rat liver. This enzyme is NADPH-dependent and aerobic, reducing the compound to 2-methyl-1,2-bis-(3-pyridyl)prop-1-ol… A second enzyme has not yet been identified…
Biological half-life
1.9 ± 0.7 hours.
The plasma half-life of metheprone is approximately 20–26 minutes.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Evidence from two patients suggests that the levels of metheprone and its active metabolites in breast milk are extremely low and unlikely to have adverse effects on breastfed infants. Avoiding breastfeeding for 2 to 2.5 hours after each dose significantly reduces the infant's drug exposure. ◉ Effects on Breastfed Infants
A postpartum woman took 250 mg metheprone three times daily, along with 10 mg bisoprolol and 12.5 mg captopril twice daily. She fed her preterm infant approximately 50% breast milk and 50% formula. Five weeks postpartum, a blood sample was collected from the infant. 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 the normal range, and the pediatric team considered the infant's growth and development to be normal.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found. Women taking metenprazole long-term for Cushing's syndrome-related hypercortisolism may have other hormonal abnormalities that may interfere with lactation.

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Interactions
Patients receiving estrogen, progesterone, corticosteroids, phenothiazines, chlordiazepoxide, chlorpromazine, amitriptyline, phenobarbital, or mexiergot may experience a low response to metenprazole. Estrogen-progestin oral contraceptives have been reported to both decrease and increase the response to metenprazole.
Pre-administration of metenprazole can induce excessive follicle-stimulating hormone (FSH) secretion following a single injection of luteinizing hormone-releasing hormone (LRH).
Metenprazole reduces metabolite production through 3-hydroxylation and N-1-demethylation, but has no effect on the C-4'-hydroxylation of diazepam.
Levodopa enhances the hypothalamic-pituitary-adrenal axis response to metheprone in patients with acromegaly.

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Safety and Tolerability[2]
Metheprone treatment was well tolerated with no serious adverse events. The incidence of minor adverse events was low (Table 5) and was primarily reported by women (mean ± standard error of reported adverse events: women, 3.32 ± 0.47; men, 2.55 ± 0.40). Nausea and headache were reported much more frequently during metheprone treatment compared to the placebo group (Fisher exact test P values were 0.037 and 0.048, respectively). Adverse events were primarily caused by serotonergic antidepressant treatment, especially in the first two weeks of treatment. Patients taking fluvoxamine reported more nausea and agitation, while patients taking nefazodone complained more often of dry mouth. We did not observe any changes in general clinical chemistry parameters.

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Safety Considerations[3]
Of the 195 patients, 48 (25%) experienced adverse events: 88% of patients were treated as outpatients, while 12% (7 out of 57 adverse events) required hospitalization for evaluation or extended hospital stay. The incidence of adverse events was 11% (4 out of 38 patients) in patients who received treatment for more than 6 months. There were no pregnant women or deaths due to adverse events. The mean dose of metheprone at the time of adverse events was 1600 mg. Gastrointestinal upset (23%) and adrenal insufficiency (7%, symptoms including dizziness and hypotension, confirmed by biochemical tests) were the most common side effects. Most adverse events (39 out of 56) occurred within 15 days of starting metheprone or after dose escalation. Gastrointestinal upset and dizziness were the main reasons for discontinuation of the drug. Treatment for patients diagnosed with adrenal insufficiency included adding glucocorticoids (to blockade replacement therapy) or temporarily using glucocorticoids while reducing the dose of metheprone. In 15% of cases, the dose of metheprone was reduced. Twelve patients (23%) temporarily or permanently discontinued metheprone; of these, 11 achieved complete symptom relief, and 1 experienced persistent but less severe symptom relief. Muscle pain present at presentation worsened during metheprone treatment but returned to pre-treatment levels after discontinuation. Symptoms of hyperandrogenemia were uncommon; hirsutism was not reported, and only one patient experienced worsening acne during treatment. Similarly, only one patient reported edema, but the causative drug was considered a calcium channel blocker. Three patients taking diabetes medication reported hypoglycemia, which was associated with improvement in hypercortisolism. Serum potassium levels were monitored and actively managed at presentation and throughout treatment. In 138 patients receiving metheprone monotherapy without other Cushing's syndrome treatment, the mean serum potassium level increased from 3.68 nmol/L to 3.90 nmol/L during treatment (P = .003) (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 with the structure 3,3-dimethylbut-2-one, where the methyl groups at positions 1 and 4 are substituted with pyridin-3-yl groups. It is a steroid 11β-monooxygenase (EC 1.14.15.4) inhibitor used to diagnose adrenocortical insufficiency. It has diagnostic, antimetabolite, and steroid 11β-monooxygenase (EC 1.14.15.4) inhibitory effects. It is used to detect hypothalamic-pituitary feedback mechanisms to diagnose Cushing's 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 also an inhibitor of glucocorticoid synthesis. Metyrapone inhibits 11β-hydroxylase, thereby inhibiting the synthesis of cortisol from 11-deoxycortisol and corticosterone from deoxycorticosterone in the adrenal gland. The disengagement of the cortisol negative feedback mechanism leads to an increase in the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland. In turn, the continued stimulation of the adrenal glands by ACTH results in the accumulation of corticosteroid precursors 11-deoxycortisol and deoxycorticosterone. These metabolites are excreted in the urine and serve as an indicator of pituitary responsiveness. It is also an inhibitor of steroid 11β-monooxygenase. It is used to detect the hypothalamic-pituitary feedback mechanism to diagnose Cushing's syndrome. See also: metheprone tartrate (salt form). Drug Indications Used as a diagnostic drug for detecting hypothalamic-pituitary adrenocorticotropic hormone (ACTH) function. Occasionally used for the diagnosis of Cushing's syndrome. Mechanism of Action The pharmacological action of metheprone is to reduce the production of cortisol and corticosterone by inhibiting the 11-hydroxylation reaction in the adrenal cortex. Elimination of the strong inhibitory feedback mechanism of cortisol leads to an increase in the production of pituitary adrenocorticotropic hormone (ACTH). Due to the sustained blocking of the enzymatic steps in the production of cortisol and corticosterone, the adrenal cortex significantly increases the secretion of its direct precursors, 11-deoxycortisol and deoxycorticosterone (weak inhibitors of ACTH release), leading to a corresponding increase in the levels of these steroids and their metabolites in the urine. These metabolites can be easily measured by detecting 17-hydroxycorticosteroids (17-OHCS) or 17-ketosteroids (17-KGS) in urine. Based on these effects, metopiramate is used as a diagnostic test, and the measurement of urinary 17-OHCS serves as an indicator of pituitary ACTH responsiveness. Metopiramate may also inhibit aldosterone biosynthesis, resulting in mild natriuresis. Metopiramate reduces cortisol production by inhibiting 11β-hydroxylation. Biosynthesis terminates at 11-deoxycortisol…in normal individuals…subsequently, adrenocorticotropic hormone (ACTH) release increases, and 11-deoxycortisol secretion…accelerates.
Oral administration of 250 mg/m² body surface area can increase plasma glucose and growth hormone concentrations in children.
Low doses can stimulate the release of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α). High doses can inhibit the release of PGF2α.
Therapeutic Uses
Meteneradon is used to test the pituitary gland's ability to respond to a decrease in plasma cortisol concentrations. Use in patients with hypothalamic-pituitary complex disorders…does not increase renal excretion of 17-hydroxycorticosteroids.
…Meteneradon was previously used in combination with spironolactone and prednisone to relieve severe edema, but…it has been superseded by more potent diuretics. …It has also been used to study lowering plasma cholesterol levels in patients with type II familial hypercholesterolemia, but there are no well-controlled clinical study results.
Meteneradon can be used to confirm the results of a dexamethasone suppression test in the differential diagnosis of adrenal hyperplasia and adrenal adenoma…but the results of this test must be interpreted with caution.
Metenprone has been used to treat hypercortisolism caused by autonomous adrenal tumors and ectopic ACTH secretion from tumors. This product is not indicated for the correction of excessive cortisol secretion in Cushing's syndrome caused by excessive pituitary ACTH secretion.
...Metenprone administration should only be used as a test of hypothalamic-pituitary function when the adrenal glands are capable of responding to ACTH...
Drug Warnings High doses of metenprone may inhibit 18- and 19-hydroxylases, thereby inhibiting the synthesis of other steroids, including estrogens. This drug may also reduce plasma cortisol half-life, increase growth hormone release, and induce hyperglycemia.
This drug may induce acute adrenal insufficiency in patients with decreased adrenal secretory function. Metenprone also inhibits aldosterone synthesis...However...it does not usually cause mineralocorticoid deficiency, leading to sodium loss and potassium retention...
Occasionally, arterial blood pressure may decrease, and a moderate tachycardia may occur. ...This drug should not be used in patients with adrenocortical insufficiency...The safety of this drug during pregnancy has not been established.
Adrenal responsiveness to adrenocorticotropic hormone (ACTH) should be confirmed before using metopiramate...
For more complete data on drug warnings for metopiramate (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
Metopiramate is an inhibitor of endogenous adrenocortical hormone synthesis.

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In summary, the results of this study clearly demonstrate that lower and higher doses of metopiramate have different effects on learning, memory, and emotional expression. These findings are consistent with the hypothesis of a dose-dependent effect of metopiramate on 692 B. Roozendaal et al. MR and GR-mediated processes. The effects of post-training injections of corticosterone and dexamethasone on memory retention in the water maze task also support this view. MR and GR are involved in different aspects of anxiety and fear-driven behavior. MR is involved in animals expressing fear in situations such as rigidity. GR appears to be more involved in the mechanisms of anxiety generalization. In the water maze experiment, MR has been shown to be involved in developing behavioral strategies for finding platforms, while GR is involved in regulating memory consolidation. [1]

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This study had limitations due to its retrospective design. In addition, there is currently no standardized monitoring and dosing regimen for patients receiving metheprone. Monitoring hypercortisol levels in patients with Cushing's syndrome receiving drug therapy is crucial to ensure that patients receive the correct dose and to identify potential adrenal insufficiency as early as possible; serum cortisol measurement can achieve this. Although this study was conducted at a university center with extensive experience in managing Cushing's syndrome (CS), the biochemical monitoring methods and monitoring frequencies varied, which affected the uniformity of the presented data. During the study, common clinical practice was to keep cortisol levels at 9 a.m. below the upper limit of normal (ULN) of the method used, or below 600 nmol/L. Any results above these levels would prompt an increase in dose or the addition of a second drug. Therefore, we used these thresholds as the standard for normalization of hypercortisol levels. Recent studies have proposed stricter standards for controlling serum cortisol levels at 9 a.m., with a recommended value below 331 nmol/L (12 µg/dL). We cannot know whether clinicians would increase the dose of metheprone if this standard were adopted; therefore, we can only speculate that the overall control effect might be better if this standard were applied in practice. In conclusion, our data suggest that metheprone is effective and safe for treating hypercortisolism in patients with Cushing's syndrome. [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.)