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PubMed1985

Influence of species, sex and drug pretreatment on the metabolism of metyrapone.

The metabolism of metyrapone was investigated in three mammalian and four non-mammalian species, and keto reduction was found to be the major metabolic route (except in the cat). Toad, lizard and tortoise did not form metyrapone N-oxides. Rat and cat formed both isomeric N-oxides of metyrapone, whereas rabbit and pigeon have a limited capacity to form only the N-oxide II and N-oxide I, respectively. There were marked sex differences in both keto reduction and N-oxidation in the rat. Anthracene did not affect metyrapone N-oxides formation in the male rat; however phenobarbitone and pregnenolone significantly induced N-oxide II formation, whereas ethanol induced both isomeric N-oxides formation. Cimetidine, a known cytochrome P-450 inhibitor, inhibited the N-oxide II formation but with an enhanced N-oxide I formation.

Animals↗
PubMed2004

Metyrapone tests in patients with panic disorder.

BACKGROUND: Studies of hypothalamic secretion of corticotropin-releasing hormone (CRH) in patients with panic disorder in the nonpanic state (using CRH tests) are contradictory. No data about the hypothalamic-pituitary response to metyrapone are available. METHODS: Study participants included 14 patients with panic disorder (DSM-IV criteria) and 14 healthy control subjects who underwent a standard overnight metyrapone test and a combined metyrapone/low-dose dexamethasone test. RESULTS: Significant treatment effects of metyrapone and combined metyrapone/dexamethasone were found on plasma corticotropin, cortisol, and 11-deoxycortisol, but no differences between patients and control subjects emerged. Considering visual analogue scale ratings of anxiety, tension, restlessness, and Beck Depression Inventory scores as covariates, no group effects were detected. CONCLUSIONS: Standard overnight metyrapone tests do not support a hypersecretion of hypothalamic CRH in panic disorder. Furthermore, no evidence for increased glucocorticoid negative feedback in panic was found. Hypothalamic CRH secretion in the nonpanic state needs further research.

Adrenocorticotropic Hormone↗
PubMed2004

Overnight metyrapone and combined dexamethasone/metyrapone tests in post-traumatic stress disorder: preliminary findings.

Using overnight metyrapone and combined dexamethasone/metyrapone tests, hypothalamic-pituitary-adrenocortical (HPA) axis feedback regulation was characterised in 10 patients with post-traumatic stress disorder (PTSD) and 10 matched healthy comparison subjects. Significant treatment effects of both metyrapone and the combination of dexamethasone and metyrapone were observed for adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11-DOC) and cortisol, but no differences between patients and comparison subjects emerged. Dose-response studies using metyrapone and glucocorticoid agonists are needed to further investigate HPA axis regulation in PTSD.

Adrenocorticotropic Hormone↗
PubMed1987

The effect of metyrapone on cytokinin ([8-14C]benzylaminopurine) metabolism in mature green tomato pericarp.

Cytokinin, [8-14C]Benzylaminopurine, metabolism in tomato pericarp was followed during a 3 h period utilizing thin layer chromatography and visualization by fluorography. Fluorography indicated the formation of at least 7 metabolites during 3 h. Cytokinin metabolism was reduced by approximately 40% in 3 h by the presence of 250 microM metyrapone, an inhibitor of cytochrome P-450 related enzyme systems. In the presence of metyrapone, the number of radioactive metabolites on the thin layer plate was reduced from 7 to 4 and 2 of these were unique to the metyrapone-treated sample. These data suggest the initial step in benzylaminopurine metabolism in tomato pericarp may be mediated by a cytochrome P-450 related enzyme system which is altered in the presence of metyrapone.

Adenine↗
PubMed2003

Action of metyrapone and tetracosactrin to modify cisplatin-induced acute and delayed emesis in the ferret.

Cisplatin 5 mg/kg, i.p., induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of metyrapone and tetracosactrin and their potential interaction. The 11beta-hydroxylase enzymes inhibitor metyrapone 10-30 mg/kg, i.p., dose dependently potentiated the acute cisplatin-induce retching+vomiting response by up to 219% at the highest dose (P<0.001) but failed to affect significantly delayed emesis (P>0.05). The adrenocorticotropic hormone (ACTH) mimetic tetracosactrin 0.1 mg/kg, i.m., antagonised significantly the acute and delayed emetic response by 98% (P<0.01) and 75% (P<0.001), respectively. The anti-emetic action of tetracosactrin on acute but not delayed emesis was prevented by combination with metyrapone 10 mg/kg, i.p. Tetracosactrin 0.1 mg/kg, i.m., failed to modify apomorphine (0.25 mg/kg, s.c.)-induced emesis. The potential anti-emetic mechanism of action of metyrapone and tetracosactrin to modulate emesis is discussed.

Acute Disease↗
PubMed1997

The corticosterone synthesis inhibitor metyrapone decreases dopamine D1 receptors in the rat brain.

Experiments were performed to examine the effect of metyrapone, an inhibitor of corticosterone synthesis, on the level of dopamine D1 receptors and their transcripts in the caudate-putamen, nucleus accumbens and olfactory tubercle of the rat brain. The binding to dopamine D1 receptors was measured by receptor autoradiography using the specific D1 receptor antagonist [3H]SCH 23390. The level of dopamine D1 receptor messenger RNA was determined by in situ hybridization histochemistry. The results obtained have shown that metyrapone (two injections of 150 and 50 mg/kg, i.p., given 20 and 3 h before killing, respectively) induced a decrease in the D1 receptor-specific binding in the studied areas of the rat brain. In the caudate putamen, the decrease in [3H]SCH 23390 binding was stronger in the medial (31-39%) than in the lateral part (24-27%). Decreases similar to those in the caudate-putamen were observed in the nucleus accumbens (21%) and olfactory tubercle (32%). Furthermore, metyrapone decreased the level of dopamine D1 receptor messenger RNA in the caudate putamen (17-28%), nucleus accumbens (20%) and olfactory tubercle (18%). In conclusion, our study indicates that glucocorticoids might be involved in the regulation of dopamine D1 receptor level in the rat brain. since metyrapone (which inhibits the synthesis of these hormones) decreases the messenger RNA encoding D1 receptor synthesis, as well as the specific binding to this receptor.

Animals↗
PubMed1987

[Adrenostatic treatment of ACTH-dependent Cushing syndrome using metyrapone and aminoglutethimide].

The adrenostatic effect of metyrapone (Metopiron) and aminoglutethimide (Orimeten) was assessed retrospectively in ten patients with ACTH-dependent Cushing's syndrome, four of them with the ectopic form. Five patients received metyrapone only, the other five both metyrapone and aminoglutethimide. Persistent lowering of the serum cortisol level was achieved in all, after an observation period of two weeks to four years. The intended therapeutic level of below 16 micrograms/100 ml was achieved in seven patients. In the course of treatment there was a rise in mean plasma ACTH concentration, but without an "escape" phenomenon. The adrenostatic treatment had to be limited, if at all, only because of side effects, which in two patients required that the drug administration be terminated. It is concluded that adrenostatic treatment with metyrapone and aminoglutethimide is effective and practical. It is suitable not only in the management of florid Cushing's syndrome, but also for long-term treatment when complete cure is not possible.

Adolescent↗
PubMedDate not supplied

A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH.

The adrenal responses to insulin-induced hypoglycemia and the rapid adrenocorticotropic hormone (ACTH) stimulation test were compared in 24 healthy volunteers, 18 of whom also underwent a rapid oral metyrapone test. The cortisol levels after hypoglycemia (18.0-30.0 microgram/100 ml) were similar to and directly related to the levels after ACTH (21.0-31.0 microgram/100 ml). The levels after both stimuli were independent of age, sex, height, and weight. The 11-deoxycortisol response to the metyrapone test was less than the cortisol response to hypoglycemia and metyrapone administration was associated with more unpleasant side effects. In a group of 69 control subjects, the post-ACTH cortisol levels were 15.0 to 80.0 microgram/100 ml while in seven patients with Addison's disease they were less than 1-4.5 microgram/100 ml. In 44 control subjects, the posthypoglycemia cortisol levels were 18.0 to 30.0 microgram/100 ml compared with less than 1.0-9.0 microgram/100 ml in 22 patients with hypopituitarism. The absolute poststimulation cortisol levels provided better separation of control subjects from patients with adrenal or pituitary insufficiency than either the increment in cortisol levels or the 11-deoxycortisol response to metyrapone.

17-Hydroxycorticosteroids↗
PubMed1993

Direct action of metyrapone on brain: implication in feeding.

While the inhibitory effect of metyrapone on the biosynthesis of adrenal corticosteroid hormones is well known, the drug has not been tested for central actions. The present study is aimed at finding out the direct central action of metyrapone, if any, employing feeding behaviour as a test parameter. Low doses of metyrapone (10-1000 ng) administered via an i.c.v. route reduced the food intake in a dose dependent manner; the effect was functionally antagonized by concomitant administration of anti-CRF antisera. The results reveal for the first time, that metyrapone might be capable of exerting a direct action on the adrenal cortex.

Analysis of Variance↗
PubMed2005

Decreased response of plasma cortisol to intravenous metyrapone in ocular hypertension and primary open-angle glaucoma.

PURPOSE: To determine if there is a difference in response to metyrapone, which blocks the conversion of 11-deoxycortisol to cortisol in the adrenal gland between normals and ocular hypertensives (OH) plus primary open-angle glaucomas (POAG) without pigmented angles. METHODS: Intravenous metyrapone was given to 20 normals and 15 ocular hypertensives plus primary open-angle glaucomas without pigmented angles. Blood samples were obtained at 4, 6, and 8 hours after administration of intravenous metyrapone for analyses of 11-deoxycortisol and cortisol. RESULTS: The ocular hypertensives plus primary open-angle glaucoma group showed significantly lower cortisol values compared with the normal group at 6 hours (P = 0.002) but not at 4 or 8 hours. There were no significant differences between the two groups for 11-deoxycortisol values at 4, 6, or 8 hours. The percent decrease of plasma cortisol from baseline was significantly greater for the ocular hypertensives plus open-angle glaucoma group compared with the normals at 4 hours (P = 0.010) and 6 hours (P = 0.0004). Significant negative correlations were observed for the total group of subjects between levels of plasma cortisol at 6 hours and intraocular pressure, worse eye (P = 0.029), percent area of cupping, worse eye (P = 0.045), pallor, worse eye (P = 0.001), and visual field loss, worse eye (P = 0.048), so that the less the plasma cortisol, the greater the abnormality of the glaucomatous parameters. Multivariate analyses with the 6-hour plasma cortisol level as the dependent variable showed that the only significant (P = 0.0004) independent variable was the percent area of pallor, worse eye, associated with a smaller level of plasma cortisol at 6 hours. Similarly, the multiple regression models using the percent change from baseline of the 6-hour plasma cortisol value showed a significant association of larger percent decreases of plasma cortisol in the ocular hypertensives plus open-angle glaucoma compared with the normals. CONCLUSIONS: The ocular hypertensives plus primary open-angle glaucoma subjects show greater adrenal inhibition to metyrapone in the synthesis of cortisol from 11-deoxycortisol compared with normals. This observation suggests an adrenal abnormality in the ocular hypertensive plus primary open-angle glaucoma subjects.

Aged↗
PubMed1977

Evaluation of 3 hour metyrapone test in children and adolescents.

An evaluation of a new 3 h metyrapone test is presented. The test consists of one oral dose of metyrapone given at 08.00-09.00 hours, and determination of plasma deoxycortisol from a single capillary blood sample taken 3 h later. The test has been assessed in children and adolescents in conjunction with a 5 day metyrapone test, insulin test, vasopressin test, and ACTH test in forty-five reference subjects, in thirty-six hypopituitary subjects with normal or deficient ACTH secretion, in three subjects with primary adrenocortical disease and in ten subjects prior to and after pharmacological prednisone medication. During the first hour after metyrapone the plasma cortisol level decreased to almost the low level maintained for the rest of the 3 h period. The plasma deoxycortisol concentration was basally less than or equal to 35 nmol/l and increased continuously during the 3 h period to the mean level of 299 (95% confidence interval 133-669) nmol/l in the reference subjects. The new test proved to be as accurate as the insulin test in detecting ACTH deficiency. No significant rise was observed in the plasma somatotrophin (GH) level in those children who had a normal GH response to insulin hypoglycaemia.

Adolescent↗
PubMed1980

Evaluation of the three hour metyrapone test in adults.

The prolonged metyrapone test is used to assess the hypothalamic-pituitary-adrenal axis. The dynamic responses of cortisol, ACTH and 11-deoxycortisol over the 3 h of the single morning dose metyrapone test have been examined in fourteen normal adult subjects. In every case there was a rapid, sustained fall in cortisol, but the resultant ACTH responses were extremely variable and in two subjects did not exceed values obtained during the control studies. The rise in 11-deoxycortisol was also variable and in several instances occurred without any significant elevation in ACTH. In these cases, the rise in 11-deoxycortisol may be due to a normal level of production of steroids with a shift from cortisol to 1-deoxycortisol induced by the metyrapone. Thus, the hypothalamic-pituitary-adrenal axis may not be adequately tested, and this together with the high incidence of unpleasant side effects, makes the 3 h oral metyrapone test unsatisfactory for routine use in adults.

Adrenocorticotropic Hormone↗
PubMed1981

Clinical response to metyrapone as indicated by measurement of mineralocorticoids and glucocorticoids in normal children.

The effect of 24-h metyrapone administration on adrenal mineralocorticoid and glucocorticoid pathways has been studied in normal children. Urine and serum steroid concentrations were evaluated. Simultaneous determinations of deoxycorticosterone (DOC), corticosterone (B), cortisol (F), and aldosterone (aldo), in both urine and serum, were carried out by celite column chromatography and radioimmunoassay. 11-deoxycortisol (Compound S) in serum and urine, urinary free 18-hydroxydeoxycorticosterone (18-OH-DOC), urinary free 18-hydroxycorticosterone (18-OH-B), and urinary aldosterone-18-glucuronide (pH 1 aldo) were measured separately by specific methods. Conclusions drawn were that (1) Useful indices of metyrapone effect were the marked rise of 11-deoxysteroids (DOC and S), and the fall of aldo and 18-OH-B; no changes occurred in 18-OH-DOC and the 11-hydroxylated steroids (B, F); (2) Serum and urine values were significantly correlated, indicating that both were equally reliable in the evaluation of the metyrapone test; (3) Hormonal ratios indicate that metyrapone inhibition affected the 11-hydroxylation of DOC and Compound S, and the 18-hydroxylation of DOC and B; and (4) The correlation between DOC/B and S/F ratios was highly significant (r = 0.86; P less than 0.0001), showing the same degree of inhibition of 11-hydroxylase functions for both 17-hydroxy (17-OHS) and 17-deoxysteroids.

Adolescent↗
PubMed1993

Elevated plasma 19-hydroxyandrostenedione levels in Cushing's disease: stimulation with ACTH and inhibition with metyrapone.

OBJECTIVE: The regulation of 19-hydroxyandrostenedione secretion has been suggested to be under the control of both the ACTH-adrenal axis and renin-angiotensin system. We undertook the present study to evaluate the effect of the chronic excess of ACTH, or the short-term excess of ACTH due to metyrapone, on 19-hydroxyandrostenedione secretion in patients with Cushing's disease. DESIGN AND PATIENTS: We measured plasma 19-hydroxyandrostenedione levels simultaneously with plasma delta 4-androstenedione, corticosterone, 11-deoxycorticosterone, aldosterone and cortisol levels after HPLC separation in 13 patients with Cushing's disease under basal conditions and during a dexamethasone suppression test or metyrapone test. Seven patients with Cushing's syndrome due to adrenal adenoma were used for comparison. RESULTS: The basal levels of 19-hydroxyandrostenedione in Cushing's disease were elevated (mean +/- SD; 323 +/- 193 pmol/l, n = 13), while those in Cushing's syndrome due to adrenal adenoma were low (92 +/- 24 pmol/l, n = 7), compared to those in normal subjects (117 +/- 33 pmol/l, n = 54). The basal levels of delta 4-androstenedione were mildly elevated in Cushing's disease (9.0 +/- 6.5 vs 3.6 +/- 2.6 nmol/l of normal subjects) but not in Cushing's syndrome due to adrenal adenoma (3.1 +/- 3.0 nmol/l). In the overnight 8 mg dexamethasone suppression test in Cushing's disease (n = 12), plasma levels of 19-hydroxyandrostenedione and delta 4-androstenedione decreased from 277 +/- 172 to 156 +/- 99 pmol/l and from 9.2 +/- 6.8 to 4.7 +/- 3.4 nmol/l, respectively, whereas the overnight 1 mg dexamethasone suppression test did not induce significant changes. Metyrapone administration in Cushing's disease (n = 9) increased plasma delta 4-androstenedione level from 9.5 +/- 6.7 to 47.2 +/- 28.1 nmol/l, but decreased plasma 19-hydroxyandrostenedione level from 301 +/- 196 to 196 +/- 105 pmol/l. CONCLUSIONS: These data indicate that plasma levels of 19-hydroxyandrostenedione in patients with Cushing's disease are elevated due to chronic ACTH excess, and that metyrapone can inhibit 19-hydroxylation in humans.

Adrenal Cortex Hormones↗
PubMed1976

Binding of a metyrapone spin label to microsomal cytochrome P-450.

Probing of the active site of microsomal cytochrome P-450 was carried out with a spin label derived from 2-methyl-1,2-bis(3-pyridyl)-1-propanone (metyrapone). Its optical binding spectra to cytochrome P-450 resemble the spectra with metyrapone. The electron paramagnetic resonance spectrum of the spin label in microsomes indicates binding with strong immobilization. Since the apparent optical and EPR binding constants agree very well (Ks approximately 2-10(-5) M), and metyrapone is found to displace the spin label, we conclude, that the spin label binds to the active site of cytochrome P-450. Addition of detergents or an increase in temperature mobilizes the bound spin label slightly. The EPR signal accounts for only 60% of the bound spin label due to its dipolar interaction with the low-spin ferric heme of cytochrome P-450. From this finding, the distance between nitroxide and iron is evaluated to be 11 A. This supports the model that one of the pyridine nitrogens of metyrapone is coordinated to the iron of cytochrome P-450. The bound spin label shows virtually no interaction with ferricyanide as if the active site of cytochrome P-450 is a hydrophobic pocket not accessible to ions.

Animals↗
PubMed1977

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing's disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing's syndrome, irrespective of aetiology.

Adolescent↗
PubMed1986

Metyrapone delays surfactant and antioxidant enzyme maturation in developing rat lung.

The surfactant system and the antioxidant enzyme system of the fetal lung have chronologically similar developmental patterns and both can be accelerated by the administration of exogenous glucocorticoids. To test whether the antioxidant enzyme system, like the surfactant system, is regulated, at least in part, by endogenous glucocorticoids, we injected pregnant rats for 3 days prior to delivery with metyrapone, an adrenal 11-beta hydroxylase inhibitor which crosses the placenta and blocks endogenous glucocorticoid synthesis, or saline. Metyrapone offspring had significantly decreased lung tissue disaturated phosphatidylcholine/total phospholipids (p less than 0.05) compared to controls at days 21 and 22 of gestation. Activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were similarly significantly reduced (p less than 0.01) in the lungs of metyrapone offspring at both gestational days studied. One day premature metyrapone pups demonstrated poorer survival than control pups from 25 min after delivery (44% survival versus 83%, p less than 0.05) to 90 min (6% survival versus 78%, p less than 0.01). These findings of delayed maturation of the surfactant and antioxidant enzyme systems following adrenal glucocorticoid blockade suggest that both systems are regulated, at least in part, by an endogenous glucocorticoid mechanism.

Animals↗
PubMed1994

Comparison of adrenocorticotropin and adrenal steroid responses to corticotropin-releasing hormone versus metyrapone testing in patients with hypopituitarism.

We compared the responses of ACTH and cortisol (F) to corticotropin-releasing hormone (CRH) administration (ovine 1 microgram/kg i.v. bolus) with the responses of urinary 17-OH corticosteroids (17-OHCS) and serum deoxycorticosterone (DOC) to metyrapone administration (450 mg/m2/dose every 4 h x seven doses) in 16 hypopituitary patients. Glucocorticoid therapy for these patients was withheld for a minimum of 3 wk before testing. The CRH test was performed 3 d before or 3 wk after the metyrapone test was used to diagnose the ACTH reserve status. In nine ACTH-intact hypopituitary patients (post-metyrapone 17-OHCS > 12.2 mumol/m2/d; DOC > or = 11.5 nmol/L), the peak F (497-773 nmol/L) and ACTH (5.2-22 pmol/L) responses to CRH stimulation were similar to those of normal subjects (F peak = 554-993 nmol/L and ACTH peak = 6-25 pmol/L at 15-60 min). In one patient with partial ACTH deficiency (postmetyrapone 17-OHCS = 10.5 mumol/m2/d; DOC = 6 nmol/L), the peak F response was low and delayed (246 nmol/L at 180 min) and the peak ACTH response was normal (7 pmol/L). Six severely ACTH-deficient patients (postmetyrapone 17-OHCS < 5.4 mumol/m2/d; DOC < or = 3.4 nmol/L) had a low F response at 15-90 min in all, with a delayed rise in three at 120-180 min in response to CRH administration, whereas ACTH responses were variable: absent or low, normal, delayed, or persistently exaggerated. In conclusion, the CRH-stimulated F response pattern in hypopituitary patients was comparable to the urinary 17-OHCS and serum DOC response to metyrapone administration.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxycorticosteroids↗