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PubMed1991

Effect of metyrapone on the timing of oviposition and ovarian steroidogenesis in the laying hen.

1. The purpose of this study was to observe the effects of metyrapone on the time of oviposition and LH-stimulated steroidogenesis by granulosa cells and small yellow follicles. 2. In experiment 1, White Leghorn hens were injected for 11 d with 240 mg metyrapone 5 h before 'lights off'. Control hens were injected with 1 ml of vehicle (PEG-400). Metyrapone treatment resulted in a 28% decrease in the rate of lay and the modal frequency of the time of oviposition was phase-shifted by 15 h. 3. In experiment 2, hens were injected with 240 mg metyrapone 5 h before 'lights off' or at 'lights on'. While metyrapone treatment reduced the rate of lay, a clear phase-shift in the distribution of oviposition was not observed. Basal and LH-stimulated progesterone synthesis by the granulosa cells of the largest follicle and oestradiol synthesis by small yellow follicles was significantly reduced. 4. Metyrapone treatment significantly reduced basal, but not LH-stimulated output of androstenedione by whole small yellow follicles compared to that observed in control hens. 5. The addition of metyrapone in vitro to isolated granulosa cells from the three largest preovulatory follicles inhibited LH-stimulated progesterone production in a dose-specific manner. 6. The results of this study suggest that the ability of metyrapone to perturb the open-period is a pharmacological effect mediated through inhibition of ovarian and adrenal steroidogenesis.

Androstenedione↗
PubMed1996

Glucocorticoid receptor-independent transcriptional induction of cytochrome P450 3A1 by metyrapone and its potentiation by glucocorticoid.

Metyrapone administration to 21- and 90-day-old male rats causes a transcriptional induction of the hepatic glucocorticoid-inducible CYP3A1 gene within an hour as determined by nuclear run-on experiments. Analyses performed 24 hr after metyrapone administration in both ages of rat demonstrate that the transcriptional induction of CYP3A1 gene expression is followed by significant increases in CYP3A1 mRNA, CYP3A-immunoreactive microsomal protein and total microsomal cytochrome P450 (CYP). In 21-day-old rats, there is a significant increase in microsomal CYP3A dependent steroid 6 beta-hydroxylase activity but not in 90-day-old rats, possibly because of a slower clearance of this drug, which inhibits CYP activities. In hepatocytes cultured in serum- and glucocorticoid hormone-free medium, metyrapone alone induces CYP3A1 mRNA expression, which demonstrates that metyrapone transcriptionally induces hepatic CYP3A1 by a direct interaction with the liver. Metyrapone does not compete with the binding of the synthetic glucocorticoid and potent transcriptional CYP3A1 inducer dexamethasone to the glucocorticoid receptor (GR) in soluble fractions from liver. This suggests that metyrapone is not a ligand for the GR and induces CYP3A1 by a mechanism independent of the GR. Addition of glucocorticoid to cultured hepatocytes at levels that induce GR-dependent genes potentiate CYP3A1 mRNA induction by metyrapone without inducing CYP3A1 mRNA alone. A GR-dependent mechanism may therefore mediate the potentiation of CYP3A1 transcriptional induction by metyrapone. The CYP3A1 transcriptional inducer and glucocorticoid antagonist pregnenolone 16 alpha-carbonitrile at 100 microM blocks dexamethasone binding to the GR in 21-day-old rat liver soluble fractions but is less effective in 90-day-old rat liver soluble fractions in contrast with 10 microM glucocorticoid antagonist RU486, which is equally effective at blocking dexamethasone binding to the GR. The inability of pregnenolone 16 alpha-carbonitrile to fully compete with dexamethasone for cytosolic binding in adult animals suggests that there may exist variant receptors with different affinities for dexamethasone and pregnenolone 16 alpha-carbonitrile and may explain the mechanism by which low concentrations of dexamethasone potentiate the transcriptional induction of CYP3A1 mediated by high concentrations of pregnenolone 16 alpha-carbonitrile [J. Biol, Chem. 270:28917-28923 (1995)]. Examination of membrane-bound dexamethasone binding activity, with which other steroidal and nonsteroidal CYP3A inducers have been shown to compete, indicates that binding activity is detectable in 90- but not 21-day-old rat liver microsomes. The absence of membrane-bound glucocorticoid binding site activity and the presence of a functional CYP3A1 transcriptional response in 21-day-old rats suggest that membrane-bound glucocorticoid binding site activity is not involved in the transcriptional activation of CYP3A1 expression. These data suggest that both glucocorticoids and nonsteroidal compounds may trigger the transcriptional induction of CYP3A1 by a GR-independent mechanism that may be potentiated by a GR-dependent mechanism.

Aging↗
PubMed2004

Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial.

BACKGROUND: Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings. OBJECTIVE: To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Hospitalized care. PATIENTS: Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression. INTERVENTIONS: Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine). MAIN OUTCOME MEASURES: Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred. RESULTS: 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.

Adrenocorticotropic Hormone↗
PubMed1985

Metyrapone: an agent for melatonin as well as ACTH and cortisol secretion.

The metyrapone-test was used to study the influence of pituitary-adrenal activity on the pineal function in man. We recorded in blood the circadian rhythmicity of melatonin, ACTH and cortisol and the excretion of melatonin, cortisol and Porter-Silber chromogens in urine before, during and after the administration of 750 mg metyrapone every 4 h during 24 h in two healthy volunteers and in two patients with asymptomatic, moderate hyperparathyroidism and a prolactin-secreting microadenoma, respectively. The present study confirmed our previous report on an increased excretion of melatonin per 24 h and per mmol creatinine during the administration of metyrapone. The excretory maximum preceded the maximal ACTH-adrenal response. Serum melatonin remained unchanged during the administration of metyrapone. A second finding was depressed serum melatonin the night after the test in the subjects with the most marked ACTH-cortisol response following the metyrapone-test indicating suppression of melatonin secretion when ACTH-cortisol secretions were increased. A third finding was a late increase in diuresis appearing the day after metyrapone-administration while glomerular filtration rates did not show significant alterations. Thus, it is shown that the metyrapone-induced cortisol inhibition stimulates both ACTH and melatonin secretion, while high ACTH and cortisol levels are accompanied by reduced S-melatonin levels.

17-Hydroxycorticosteroids↗
PubMed1984

Effects of metyrapone and norharmane on microsomal mono-oxygenase and epoxide hydrolase activities.

This study was undertaken to examine the possibility that metyrapone and norharmane stimulate epoxide hydrolase and inhibit mono-oxygenase activities by binding to a cytochrome P-450 component of a stable complex containing the two enzymes. The concentration of metyrapone and norharmane which inhibited mono-oxygenase activities of hepatic microsomes from untreated and diethylnitrosamine treated rats was lower than that required to stimulate epoxide hydrolase of the same microsomes. The ability of metyrapone and norharmane to stimulate epoxide hydrolase in these microsomes was not inhibited by the addition of carbon monoxide and reductant. Epoxide hydrolase activity was inhibited by detergents but the enzyme was still stimulated by metyrapone and norharmane under conditions of total membrane disaggregation. When microsomes were solubilized, epoxide hydrolase could be quantitatively recovered by immunoprecipitation. The immunoprecipitate contained no detectable cytochrome P-450 but was stimulated by metyrapone and norharmane. A purified epoxide hydrolase was stimulated by metyrapone but not by norharmane. The response of the enzyme to norharmane was not restored by the inclusion of cytochrome P-448. These findings suggest that metyrapone and norharmane act at separate sites on both cytochrome P-450 and epoxide hydrolase.

Alkaloids↗
PubMed1991

Carbonyl reduction of metyrapone in human liver.

Carbonyl reduction was investigated in cytosolic and microsomal fractions of human liver using the ketone metyrapone as a substrate. The cytosolic enzyme has a stronger preference for NADPH over NADH than the microsomal enzyme: the former shows only 14% of the NADPH-supported activity while the latter exhibits 36% activity with NADH. Barbitone and quercitrin, the classic inhibitors of carbonyl reductases, do not affect metyrapone reduction in either fraction. Dicumarol and indomethacin, the specific inhibitors of NAD(P)H: quinone-oxidoreductase and dihydrodiol dehydrogenase, respectively, only slightly decreased metyrapol formation. In contrast, 5 alpha-dihydrotestosterone, the active form of the androgen steroid testosterone, inhibited metyrapone reduction very strongly in the microsomal fractions and is postulated to be the physiological substrate of the enzyme. This resembles the situation in mouse liver [E. Maser and K. J. Netter, Biochem Pharmacol 38: 3049-3054, 1989] where microsomal metyrapone reductase was inhibited by steroids and the purified enzyme was demonstrated to mediate androsterone oxidation. Immunoblot analysis revealed antigenic cross-reaction of antibodies against the 34 kDa metyrapone reductase from mouse liver microsomes with the homologous protein in human liver microsomes pointing to structural homologies between the respective enzymes of the two species. These results--together with previous findings, which have shown that there exist functional as well as structural relationships between microsomal mouse liver metyrapone reductase and 3 alpha-hydroxysteroid dehydrogenase from Pseudomonas testosteroni [E. Maser, U. Oppermann and K. J. Netter, Eur J Pharmacol 183:1366, 1990]--suggest that metyrapone reduction in human liver microsomes might be catalysed by a microsomal hydroxysteroid dehydrogenase.

Alcohol Oxidoreductases↗
PubMed2006

Metyrapone improves endothelial dysfunction in patients with treated depression.

OBJECTIVES: This study sought to examine the effect of metyrapone on endothelial dysfunction in patients with treated recurrent major depression. BACKGROUND: Depression is an independent risk factor for the development of coronary heart disease, and patients with depression have endothelial dysfunction, an atherogenic abnormality. This abnormality may be attributable to abnormal hypothalamic-pituitary-adrenal (HPA) axis function, a feature of depression, resulting in increased exposure to cortisol. Cortisol administration produces endothelial dysfunction in healthy subjects. METHODS: We measured endothelial function using flow-mediated dilation (FMD) of the brachial artery in 30 patients with depression and in 36 matched control subjects. Patients were randomized (double blind) to metyrapone (an inhibitor of cortisol synthesis) or placebo, and FMD was remeasured 6 h later. RESULTS: At baseline, FMD was impaired in patients versus control subjects (mean [standard error]), -1.27% [0.91%] vs. 4.37% [0.59%] (p < 0.001). The FMD was similar in the placebo and the metyrapone patient groups at baseline (0.17% [1.04%] vs. -2.72% [1.30%], p = 0.11). Metyrapone significantly reduced plasma cortisol levels. There was a significant improvement in FMD in the metyrapone group from -2.72% [1.30%] to 3.82% [0.99%] (p < 0.001), whereas the change in the placebo group, from 0.17% [1.04%] to 1.15% [1.14%], was not significant. Analysis of covariation showed that the effect of metyrapone was significant (p = 0.034). CONCLUSIONS: Inhibition of cortisol production by metyrapone ameliorates the endothelial dysfunction seen in depression, suggesting that the mechanism of the endothelial dysfunction may involve cortisol.

Adult↗
PubMed1996

Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory.

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.

Adrenal Cortex↗
PubMed1997

Metyrapone pre-treated inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful investigative technique in the differential diagnosis of ACTH-dependent Cushing's syndrome. Diagnostic accuracy is improved by the administration of corticotrophin releasing-factor (CRF) during the procedure to stimulate ACTH secretion. We hypothesized that, given the unavailability of CRF in Australia, stimulation of ACTH secretion from tumorous corticotrophs with metyrapone treatment before IPSS may be useful. AIMS: To describe our clinical experience with a novel diagnostic test, and to compare results between IPSS with and without metyrapone pre-treatment. SETTING: Metropolitan, Australian university teaching hospital. PATIENTS: 18 patients were studied on 21 occasions: three with Cushing's disease without metyrapone treatment prior to IPSS (M-), 11 with Cushing's disease with metyrapone pretreatment (M+), three with ectopic ACTH syndrome, and one with pseudo-Cushing's syndrome. TREATMENT: Patients received oral metyrapone, median dose 750 mg 6 hourly, for 24 h before IPSS. RESULTS: No major side effects were noted. Metyrapone increased serum 11-deoxycortisol concentration to a median of 400 nmol/l (range 36-1310) on the morning of the test. Radiological confirmation of correct catheter placement was shown in 36/42 inferior petrosal sinuses (86%). Median peak central: peripheral ACTH ratios were 9.8 for M- pituitary adenomas (range 5.7-13.6), 12.9 for the technically successful M+ pituitary adenomas (range 8-54.1), and 1.6 for M+ ectopic ACTH syndrome cases (range 1.2-3.4). Repeat studies in unoperated patients with ectopic ACTH syndrome showed ratios < 1.6. IPSS showed median peak ACTH concentrations of 190 ng/l for M- pituitary adenomas (range 83-205), 595 ng/l for the technically successful M+ pituitary adenomas (range 80-7630; P = 0.035 compared to M-), and 62 ng/l for M+ ectopic ACTH syndrome cases (range 47-220). IPSS correctly identified the pituitary source of ACTH production in all cases of Cushing's disease (except one technical failure where MRI revealed a lesion). MRI scanning correctly identified a lesion in 3/14 operated Cushing's disease cases. IPSS correctly lateralized 1/3 M- and 7/8 M+ Cushing's disease cases where the procedure was technically successful and surgical descriptions adequate. Pituitary exploration revealed a visible lesion in 75% of cases corresponding to the side predicted by IPSS; 'blind' hemi-hypophysectomy was performed on the side predicted from IPSS in the remainder. All cases of Cushing's disease were cured or improved following surgery, with a median follow-up of 2.8 years (range 0.7-5.9). CONCLUSIONS: Metyrapone pre-treated inferior petrosal sinus sampling is safe, and appears to induce high ACTH output from pituitary corticotroph adenomas. The technique has allowed accurate localization and treatment of pituitary corticotroph microadenomas.

ACTH Syndrome, Ectopic↗
PubMed2000

The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery.

OBJECTIVE: To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis posthypophysectomy. DESIGN: Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4-6 weeks after pituitary surgery. SUBJECTS: Thirty-two patients with known pituitary disease. None with present or previous Cushing's syndrome. OUTCOME MEASUREMENTS: Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11-deoxycortisol level following a weight related oral dose of metyrapone at 0000 h. RESULTS: One of the 32 patients required further surgery and was studied twice after each operation. Thirty-three results are therefore compared. Twenty-six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11-deoxycortisol level less than 200 nmol/l). After 3-40 months (median 20 months) of follow-up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test. CONCLUSIONS: The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow-up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow-up to date would not support this.

Adenoma↗
PubMed2003

Metyrapone-induced glucocorticoid depletion modulates tyrosine hydroxylase and phenylethanolamine N-methyltransferase gene expression in the rat adrenal gland by a noncholinergic transsynaptic activation.

The hypothalamic corticotropin-releasing hormone system and the sympathetic nervous system are anatomically and functionally interconnected and hormones of the hypothalamic-pituitary-adrenocortical axis contribute to the regulation of catecholaminergic systems. To investigate the role of glucocorticoids on activity of the adrenal gland, we analysed plasma and adrenal catecholamines, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression in rats injected with metyrapone or dexamethasone. Metyrapone-treated rats had significantly lower epinephrine and higher norepinephrine production than control rats. Metyrapone increased TH protein synthesis and TH mRNA expression whereas its administration did not affect PNMT mRNA expression. Dexamethasone restored plasma and adrenal epinephrine concentrations and increased PNMT mRNA levels, which is consistent with an absolute requirement of glucocorticoids for PNMT expression. Adrenal denervation completely abolished the metyrapone-induced TH mRNA expression. Blockage of cholinergic neurotransmission by nicotinic or muscarinic receptor antagonists did not prevent the metyrapone-induced rise in TH mRNA. Finally, pituitary adenylate cyclase activating polypeptide (PACAP) adrenal content was not affected by metyrapone. These results provide evidence that metyrapone-induced corticosterone depletion elicits transsynaptic TH activation, implying noncholinergic neurotransmission. This may involve neuropeptides other than PACAP.

Adrenal Glands↗
PubMed2004

Differential actions of metyrapone on the fetal pituitary-adrenal axis in the sheep fetus in late gestation.

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1983

Suppressive effect of metyrapone on plasma corticotrophin immunoreactivity in normal man.

Short term alterations of plasma corticotrophin immunoreactivity (ACTH) and cortisol were studied in healthy men under basal conditions and during intravenous administration of metyrapone. In the intravenous experiment, a low dose (1 g/5 h) and a high dose (4 g/5 h) of metyrapone ditartrate were infused. In the early phase of the metyrapone experiments, plasma ACTH fell from 9.46 +/- 0.95 (SE) pmol/l at 08.00 h to 7.7 +/- 1.1 pmol/l at 09.00 h (P greater than 0.05) in the low-dose experiment, and from 7.0 +/- 1.6 pmol/l to 4.6 +/- 0.9 pmol/l (P less than 0.05) in the high-dose experiment. A significant delayed increase of plasma ACTH secondary to the hypocortisolaemic stimulus was apparent in the high-dose experiment, in which plasma cortisol was maximally suppressed to 14 +/- 3 nmol/l at 13.00 h. No significant increase was observed in the low-dose experiment, the maximal suppression of plasma cortisol being 46 +/- 9 nmol/l at 14.00 h. The present data suggest dual effects of metyrapone on plasma ACTH: 1) a suppressive effect, the mechanism of which is not yet understood, and 2) the known increasing effect of 'feed-back' stimulation, which seems to be very sensitive to alterations of plasma cortisol only at cortisol levels lower than about 50 nmol/l. The suppressive effect of metyrapone may account for the frequently described inadequate response of plasma ACTH to metyrapone-induced hypocortisolaemia. Particularly, the diagnostic validity of the very short versions of the metyrapone test would seem to be seriously questioned.

Adrenocorticotropic Hormone↗
PubMed1985

Multiple-sites of inhibition by intravenous metyrapone of human adrenal steroidogenesis.

The in vivo influence of metyrapone on adrenal steroidogenesis has been studied by measuring plasma concentrations of pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone, 11-deoxycorticosterone, 11-deoxycortisol, corticosterone, cortisol, 18-OH-11-deoxycorticosterone, 18-OH-corticosterone and aldosterone before, during and after a 5 h infusion of metyrapone ditartrate at doses of 0.2 g/h and 0.8 g/h respectively. Time courses of plasma steroids and corticotrophin indicate an inhibitory effect of metyrapone on total adrenal steroidogenesis in addition to the known inhibition of the 11- and 18-monooxygenase. The effect on total adrenal steroidogenesis is pronounced at high concentrations of metyrapone and may be compensated by corticotrophin. This effect and a concomitant suppressive effect of metyrapone on plasma corticotrophin itself may account for the frequently described falsely abnormal responses to the metyrapone test. From the present 'in vivo' data, no significant, metyrapone induced alterations of the 3 beta-hydroxysteroid dehydrogenase/delta 5-isomerase, 17-monooxygenase, 21-monooxygenase or the 18-hydroxysteroid dehydrogenase are apparent.

17-alpha-Hydroxypregnenolone↗
PubMed1994

The metyrapone and dexamethasone suppression tests for the differential diagnosis of the adrenocorticotropin-dependent Cushing syndrome: a comparison.

OBJECTIVE: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test. DESIGN: Retrospective cohort study. SETTING: Inpatient research ward. PATIENTS: 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH. MEASUREMENTS: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used. MAIN RESULTS: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively. CONCLUSIONS: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.

Adrenocorticotropic Hormone↗
PubMed2000

Effect of the adrenal 11-beta-hydroxylase inhibitor metyrapone on human hepatic cytochrome P-450 expression: induction of cytochrome P-450 3A4.

The drug metyrapone in the presence of glucocorticoid has been shown to induce the expression of rat hepatic cytochrome P-450 (CYP) 1A1 mRNA in vivo and in vitro through disruption of endogenous CYP1A1 regulator homeostasis and without either compound's binding to the aryl hydrocarbon receptor. Addition of metyrapone to human liver cancer cell cultures, with or without dexamethasone, did not induce CYP1A1 mRNA, in contrast to the aryl hydrocarbon receptor ligand beta-naphthoflavone. Addition of metyrapone to primary cultures of human hepatocytes also failed to induce detectable levels of CYP1A1 mRNA or CYP1A protein in two separate preparations, whereas the treatment with 2,3,7,8-tetrachlorodibenzo-rho-dioxin or omeprazole induced detectable levels of CYP1A1 mRNA in one preparation and CYP1A protein in both preparations. Addition of metyrapone to human hepatocyte cultures resulted in the induction of CYP3A4 expression. The pregnane X receptor (PXR), which has recently been shown to mediate the transcriptional induction of CYP3A4 expression in response to rifampicin, was activated by metyrapone in CV-1 cells transiently cotransfected with an expression vector encoding the human PXR and a reporter construct containing the everted repeat sequence that confers CYP3A4 induction responsiveness to inducers within its promoter. Metyrapone activated the human PXR at concentrations that also resulted in the induction of CYP3A4 in human cultured hepatocytes. Metyrapone treatment is therefore unlikely to result in the induction of CYP1A1 but may induce the expression of CYP3A4 in humans.

Animals↗
PubMedDate not supplied

Suppression of acetaminophen conjugation and of conjugate elimination in the rat by metyrapone, a classical P-450 inhibitor.

This study examined the effects of metyrapone on the overall elimination of acetaminophen and on the individual processes principally responsible for elimination, the formation of acetaminophen sulfate and glucuronide. Because acetaminophen pharmacokinetics are nonlinear above a threshold dose, experiments were designed to investigate acetaminophen elimination in the linear (30 mg/kg) and nonlinear (150 mg/kg) ranges to assess possible effects of metyrapone on conjugating enzymes and on cofactor availability. Prior treatment with 400 mg/kg metyrapone tartrate decreased total clearance of acetaminophen over 30% in the linear range (25.4 +/- 2.0 vs. 36.2 +/- 3.7 ml/min/kg in controls; p less than 0.01) and over 40% in the nonlinear range of disposition (4.42 +/- 1.07 vs 7.76 +/- 1.37 ml/min/kg in controls, p less than 0.01). Partial clearance to acetaminophen glucuronide was decreased by metyrapone in each dose range. Partial clearance to acetaminophen sulfate also declined in each dose range but statistically so only after 150 mg/kg. Metyrapone decreased the renal clearance of acetaminophen sulfate and glucuronide when these conjugates were formed in vivo after acetaminophen administration. However, metyrapone failed to impair the renal clearance of acetaminophen glucuronide when preformed metabolites were administered directly. The utility of metyrapone as a specific inhibitor of oxidative drug metabolism appears to be limited for drugs such as acetaminophen by concomitant inhibition of competing conjugation pathways, which account for the majority of drug elimination.

Acetaminophen↗
PubMed1999

Metyrapone displays antidepressant-like properties in preclinical paradigms.

A possible involvement of glucocorticoids in the aetiology of depression is suggested by commonly reported hypothalamo-pituitary-adrenocortical (HPA) axis abnormalities in depressed patients, the modulation of the HPA axis by antidepressant drugs and clinical reports of antidepressant efficacy with antiglucocorticoid agents. The effects of treatment with metyrapone, a glucocorticoid synthesis inhibitor, and the tricyclic antidepressant, desipramine, in two rodent models of depression, namely the forced swim test and olfactory bulbectomized (OB) rat, were investigated. In addition, the effect of chronic metyrapone and desipramine treatments on the hypothermic response to a challenge with the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was assessed. There is experimental evidence to suggest that attenuation of the hypothermic response to this agonist occurs following chronic antidepressant treatment. In the forced swim test, metyrapone (50 mg/kg) and desipramine (10 mg/kg) significantly reduced the immobility time. In the olfactory bulbectomized rat model of depression, chronic administration (14 days) of metyrapone (50 mg/kg b.i.d.) and desipramine (5 mg/kg b.i.d.) attenuated the OB-related hyperactivity in a novel stressful environment. Chronic metyrapone treatment (50 mg/kg b.i.d.) attenuated the hypothermic response to an acute challenge with 8-OH-DPAT (0.05 mg/kg s.c.), indicating a change to the sensitivity of 5-HT1A receptors. These preclinical tests demonstrate an antidepressant-like profile for metyrapone. Further exploration of the therapeutic potential and possible mechanism of action of glucocorticoid antagonism in depression is warranted.

8-Hydroxy-2-(di-n-propylamino)tetralin↗