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PubMed1980

Improved single-dose metyrapone test.

One dose of metyrapone (1.5 g) administered at 6 AM, with subsequent measurement of plasma ACTH, 11-deoxycortisol, or 17-hydroxycorticosteroids (17-OHCS) (cortisol + 11-deoxycortisol) at noon and 2 PM allowed an accurate assessment of the pituitary-adrenal reserve. Eighteen subjects with a normal pituitary-adrenal reserve were studied before and after the administration of this single metyrapone dose. By noon, plasma ACTH rose from a premedication value of 39 +/- 22 (SD) to 193 +/- 104 pg/ml and 11-deoxycortisol, from 0.0 +/- 0.3 (SD) to 9.0 +/- 2.7 microgram/dl. By 2 PM, plasma 17-OHCS had increased from a premedication value of 5.0 +/- 1.5 (SD) to 16.0 +/- 1.8 microgram/dl. The differences between pre- and postmedication values were statistically significant for all indices measured (P less than 0.001). No overlap was found between values before and after metyrapone. This protocol eliminates the need for metyrapone administration every 4 h over a 24-h period. It offers the advantage of low dose and low toxicity. The integrity of the pituitary-adrenal axis can be demonstrated by measuring either plasma ACTH and 11-deoxycortisol or even 17-OHCS 6 to 8 h after the administration of this single metyrapone dose.

17-Hydroxycorticosteroids↗
PubMedDate not supplied

[ACTH response to 24 hours oral metyrapone test in normal children (author's transl)].

A study of ACTH response to orally given metyrapone were carried out with 32 normal subjects aged 18 months to 15. Effectiveness of adrenal inhibition was supported by delta F > 5 microgram or cortisol level after metyrapone < 3 microgram/100 ml. The strong positive correlation between delta F and delta ACTH indicates the high sensibility of delta ACTH as an index of the responsiveness. No correlation was found between delta ACTH and weight, height, or age. Mean level (M +/- 2 SEM) are established: plasma ACTH level at 8 before metyrapone = 32,1 +/- 7,5 pg/ml; plasma ACTH level at 8 after metyrapone = 271,8 +/- 57 pg/ml; delta ACTH = 240 +/- 6 pg. Including these considerations, biological ACTH variability, and reproductibility of determinations, an abnormal response seems to be proved by plasma ACTH level at 8 after metyrapone < 100 pg/ml or/and delta ACTH < 70 pg. A normal response is established by delta ACTH > 150 pg.

17-Hydroxycorticosteroids↗
PubMed1996

Differential induction of mRNA expression of cytochromes P450 (CYP2B1 and CYP1A1/2) by metyrapone in primary rat hepatocyte cultures.

The mRNA expression of members of two cytochrome P450 (CYP) gene subfamilies involved in carcinogen activation, the CYP1A1/2 and CYP2B1 forms, was determined in primary rat hepatocyte cultures in response to metyrapone and to the inducer phenobarbital or 5,6-benzoflavone (BNF), respectively. Incubation of cells with 0.5 mM metyrapone resulted in accumulation of CYP1A1 and CYP1A2 mRNA and in a marked increase in CYP1A-associated enzymatic activity as determined by deethylation of ethoxyresorufin. Metyrapone and phenobarbital in combination acted synergistically in elevation of ethoxyresorufin O-deethylase activity. In hepatocytes treated with metyrapone or with phenobarbital, accumulation of CYP2B1 mRNA levels preceded an increase in CYP2B-associated, pentoxyresorufin O-depentylase activity. However, CYP2B1 mRNA levels were first detectable after 24 hours of treatment with phenobarbital, whereas metyrapone elicited a substantial increase in mRNA levels within 14 hours, suggesting differing mechanisms leading to accumulation of CYP2B1 mRNA under the two inducers.

Animals↗
PubMed1988

The combined use of sodium valproate and metyrapone in the treatment of Cushing's syndrome.

We have investigated the combined use of metyrapone and sodium valproate in the treatment of five cases of dexamethasone-suppressible Cushing's disease and one case with dexamethasone non-suppressible disease. Metyrapone alone reduced 24 h urinary free cortisol (UFC) and plasma cortisol concentrations. Addition of sodium valproate to metyrapone produced a further reduction in these values in five of six patients with a reduction in plasma ACTH in three of five patients who had dexamethasone-suppressible disease. Plasma 11-deoxycortisol increased markedly on metyrapone. However, addition of valproate produced a further rise in 11-deoxycortisol values in four of five patients including the patient with dexamethasone non-suppressible disease. The results suggest that valproate may be a useful addition to metyrapone in the medical treatment of some patients with Cushing's syndrome and that it may have an action both at the hypothalamus and peripherally.

Adrenocorticotropic Hormone↗
PubMed1987

Decrease of ocular pressure with oral metyrapone. A double-masked crossover trial.

To examine the effect of a decrease in plasma cortisol level on intraocular pressure, 14 subjects with elevated ocular pressure were given oral metyrapone tartrate (an inhibitor of adrenal cortisol biosynthesis) and a placebo in a double-masked, two-period, crossover trial. Ocular pressure and the adrenal response were monitored over a seven-hour period. The decrease in ocular pressure after metyrapone administration was significantly greater than that after placebo. The 14 subjects could be designated as responders or nonresponders by decline of ocular pressure after metyrapone administration compared with response after placebo. The responders could be further differentiated from the nonresponders by a smaller decrease in ocular pressure over time in response to the placebo and by a smaller decrease over time of plasma cortisol level in response to metyrapone. These results provide further evidence that plasma glucocorticoids may play a role in the regulation of ocular pressure.

Administration, Oral↗
PubMed2002

Determination of the plasma levels of metyrapone and its enantiomeric metyrapol metabolites by direct plasma injection and multidimensional achiral-chiral chromatography.

The development and validation of a direct injection high-performance liquid chromatographic (HPLC) method, with column switching, for the determination of metyrapol enantiomers and metyrapone in human plasma is described. The system used in this work was composed of a restricted access media (RAM) bovine serum albumin (BSA) octyl column coupled to an amylose tris(3,5-dimethoxyphenylcarbamate) chiral column. Water was used as eluent for the first 5 min at a flow rate of 1.0 ml/min for the elution of the plasma proteins and then acetonitrile-water (30:70 v/v) for the transfer and analysis of metyrapol enantiomers and metyrapone, which were detected by UV at lambda = 260 nm. The total analysis time was about 32 min. The calibration curves for each enantiomer and for the metyrapone were linear in the ranges 0.075-0.75 microg/ml and 0.150-1.50 microg/ml, respectively. Recoveries, intra- and interday precision and accuracy were determined using three quality controls, one low (0.18 microg/ml), one medium (0.75 microg/ml), and one high (1.35 microg/ml) plasma concentration. Quantitative recoveries and good precision and accuracy were obtained. The limit of quantitation were 0.045 microg/ml for both enantiomers and for the metyrapone.

Calibration↗
PubMed1987

Pharmacokinetic consequences and toxicologic implications of metyrapone-induced alterations of acetaminophen elimination in man.

This study examined the effect of metyrapone on the elimination rate of acetaminophen and on the apparent formation rate of acetaminophen metabolites in man. Metyrapone treatment, 1.5 g, increased the half-life of acetaminophen, decreased the fraction of the dose recovered in the urine as the glucuronide and increased the fraction of the dose recovered in urine as the sulfate and mercapturate conjugates. The apparent rate constant for the formation of acetaminophen glucuronide was significantly decreased by metyrapone while the apparent rate constants for the formation of the sulfate and mercapturic acid metabolites were unchanged or slightly increased, respectively. These data indicate that metyrapone inhibits acetaminophen glucuronidation and possibly enhances the oxidation of acetaminophen to its quantitatively minor yet highly toxic reactive metabolite. The extent to which the parallel pathways of acetaminophen elimination are also affected by inhibitors of cytochrome P-450-mediated oxidation will limit the efficacy of these types of potential antidotes for the treatment of acetaminophen overdose.

Acetaminophen↗
PubMed1985

Effects of etomidate on cortisol biosynthesis in isolated guinea-pig adrenal cells: comparison with metyrapone.

The effects of the iv hypnotic etomidate on cortisol biosynthesis have been investigated in short term incubations of dispersed guinea-pig adrenal cells and were compared with those produced by metyrapone. Fifty percent inhibition of cortisol output was obtained at a final medium concentration of 3.5 10(-8) M (basal), 2.8 10(-8) M (ACTH-stimulated) for etomidate and of 5.10(-7) M (stimulated) for metyrapone. In the presence of etomidate, 11-deoxycortisol at 5.10(-8) M reached a peak value of 244 +/- 11% of control (mean +/- SE, n = 7). 17 alpha-Hydroxyprogesterone and progesterone were not significantly affected up to 10(-7) M, but at higher concentrations, all three precursors fell under their control values. Metyrapone induced a progressive rise of 11-deoxycortisol, from 10(-7) M upwards, to a maximum level at 10(-5) M (210 +/- 15% of control, mean +/- SE, n = 5). 17-Hydroxyprogesterone and progesterone concentrations were not significantly modified by metyrapone. The less active hypnotic L-enantiomer of etomidate had almost no inhibitory effect on cortisol production. The results obtained so far suggest that etomidate is a potent inhibitor of the mitochondrial cytochrome P-450 enzymes of the adrenal cortex, mainly the 11 beta-hydroxylase. At higher dose the cholesterol side-chain cleavage enzyme system seemed also to be affected.

17-alpha-Hydroxyprogesterone↗
PubMed1988

Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone.

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1983

The superiority of the metyrapone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

Differentiating the cause of Cushing's syndrome traditionally has depended upon measuring the response of 24-hour urine samples of cortisol or glucocorticoid metabolites to the high-dose (8 mg per day) dexamethasone test. The metyrapone test, however, is more convenient because it is a shorter test and requires the obtainment of serum samples, which can be collected more simply and more reliably than 24-hour urine samples. The usefulness of these two tests has not been adequately evaluated in a large series of patients with Cushing's syndrome. This study prospectively evaluated the accuracy of the dexamethasone and metyrapone tests in determining the cause of Cushing's syndrome in a series of 25 unselected patients. The diagnostic accuracy of these tests was calculated as follows: diagnostic accuracy = true positives and true negatives/study population X 100. Results of this study demonstrated that the metyrapone test was more accurate than the dexamethasone test in differentiating Cushing's disease from adrenocortical neoplasm (diagnostic accuracy, 100 percent versus 81 percent). All patients with Cushing's disease had a normal postmetyrapone 11-deoxycortisol concentration (greater than 10 micrograms/dl), while all patients with adrenocortical neoplasm had a suppressed 11-deoxycortisol concentration (less than 10 micrograms/dl). Thus, this study demonstrates that the metyrapone test is superior to the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

Adolescent↗
PubMed1988

Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor.

Cushing's syndrome due to bronchial carcinoid tumors that secrete adrenocorticotropin (ACTH) may be difficult to distinguish from pituitary Cushing's disease, since the responses to dexamethasone and metyrapone are sometimes similar. Recently, the ACTH and cortisol responses to ovine corticotropin-releasing factor (oCRF) have been shown to be different in pituitary Cushing's disease than in Cushing's syndrome due to other causes. It is not known if the response to oCRF can distinguish pituitary Cushing's disease from those ACTH-secreting bronchial carcinoid tumors that respond to dexamethasone and metyrapone. A case of Cushing's syndrome due to an ACTH-secreting bronchial carcinoid is described in which the responses to dexamethasone, metyrapone, and oCRF were indistinguishable from the responses observed in pituitary Cushing's disease. A bronchial carcinoid tumor should be considered even when responses to dexamethasone, metyrapone, and oCRF suggest pituitary Cushing's disease.

ACTH Syndrome, Ectopic↗
PubMed1985

Cytochrome P-450 ligands: metyrapone revisited.

Expressing metyrapone interactions with ferrous cytochrome P-450 as ligand saturation by cytochrome, rather than the more conventional cytochrome saturation by ligand, an extinction coefficient of 68.5 +/- 1.8 mM-1 cm-1 for the metyrapone complex of dithionite-reduced rat hepatic microsomal cytochrome P-450 was derived. Utilizing this new extinction coefficient, the increased cytochrome P-450 present after phenobarbital induction was almost exclusively that which is able to both bind to metyrapone and form a metabolic-intermediate complex from norbenzphetamine. However, it was not the only subpopulation present in microsomes that was able to bind metyrapone, nor the only one capable of forming a metabolic intermediate complex from norbenzphetamine. Thus, neither technique alone can be used to quantitate the "phenobarbital-induced form" of cytochrome P-450.

Animals↗
PubMed1987

Oxytocin reduces metyrapone-induced ACTH secretion in human subjects.

The inhibitory action of oxytocin (OT) on adrenocorticotropin (ACTH) secretion has been disputed. Thus we evaluated the effect of exogenous OT on the elevated blood ACTH levels in normal human subjects. Metyrapone, a blocker of cortisol secretion, was given to enhance ACTH release. This experimental model was chosen because metyrapone-induced ACTH activation depends on diminution of the negative feed-back of cortisol, which is an important physiological mechanism in the control of ACTH secretion. A striking decline in plasma cortisol levels and a 10-fold rise in the mean plasma ACTH concentration was observed within 20 h after the beginning of metyrapone treatment (750 mg orally every 4 h). The administration of OT (2 IU as a i.v. bolus plus 4 IU infused in 2 h) significantly reduced the metyrapone-induced plasma ACTH rise. Since the effect of OT was evident when ACTH secretion was enhanced by a reduced cortisol-dependent negative feed-back, confirmation of the inhibitory action of OT on the ACTH secretory system in man is provided.

Adrenocorticotropic Hormone↗
PubMed1985

Central serotonergic responses and behavioural adaptation to repeated immobilisation: the effect of the corticosterone synthesis inhibitor metyrapone.

Rats were immobilised for 2 h/day. Twenty-four hours after the 1, 3 or 7 immobilisation periods they were injected with the 5HT agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT; 5 mg/kg i.p.) and behavioural responses (i.e. hind limb abduction, forepaw treading, head weaving, tremor, Straub tail) compared with those of a control group. As we have previously observed after 7 (but not after 1 or 3 immobilisations) forepaw treading and tremor were enhanced and the other responses unaffected. Pretreatment with metyrapone (a corticosterone synthesis inhibitor 150 mg/kg i.p., 3 h before each immobilisation) did not affect the above responses to 1 immobilisation, increased tremor after 3 immobilisations and also increased forepaw treading, hind limb abduction and Straub tail after 7 immobilisations but decreased head weaving under the latter conditions. Metyrapone without immobilisation had no effect on responses to 5MeODMT. Twenty four hours after 1 or 3 (but not 7) immobilisation periods, rats placed for the first time in an open field showed less locomotion and rearing and more defaecation than control animals. Rats also given metyrapone exhibited normal open field behaviour after only 3 immobilisations. The drug also accelerated the return to normal on repeated immobilisation of the impairment of food intake and growth rate which occurred after a single immobilisation. The results as a whole suggest that metyrapone promotes behavioural adaptation to repeated immobilisation and that this is associated with enhanced postsynaptic responses to 5HT. These findings suggest that immobilisation stress-induced changes might be relevant as an animal model for depression which incorporates reported biochemical abnormalities in the illness and is of relevance to proposals concerning its precipitation by stress.

Adaptation, Physiological↗
PubMed1985

Inhibition of soybean lipoxygenase by SKF 525-A and metyrapone.

To determine whether agents which inhibit cytochrome P-450 enzymes also inhibit lipoxygenase, the effects of metyrapone and SKF 525-A were assessed on soybean lipoxygenase using a spectrophotometric technique which allows for measurement of both the rate and magnitude of product formation. Both SKF 525-A and metyrapone inhibited the rate of product formation and the final amount of product formed in 5 min incubations SKF 525-A was 5 to 5 times more potent than metyrapone, with the IC50 for SKF 525-A 40 microM and for metyrapone between 150 and 200 microM as determined by the total product formation in 5 minutes. Analysis of the reduced product by HPLC confirmed that the substances monitored were those generated by the 15-lipoxygenase enzyme.

Chromatography, High Pressure Liquid↗
PubMed1983

Facilitation of estrogen-induced receptivity through metyrapone administration in ovariectomized rats.

Previously it has been established that adrenalectomy facilitates lordosis in estrogen-primed ovariectomized female rats and that corticosterone administration restores lordosis to preadrenalectomy levels. The present study examined the effects of an inhibitor of the synthesis of corticosterone, metyrapone, upon lordosis in ovariectomized females. In Experiment 1, chronic administration of moderate doses of metyrapone was found to facilitate lordosis. In Experiment 2, a single metyrapone administration at various doses and time intervals before testing had a mild facilitatory effect on lordosis. Experiment 3 compared the effects of metyrapone on ovariectomized and adrenalectomized-ovariectomized females. The absence of a facilitatory effect in adrenalectomized females suggests that the drug's effect on lordosis is mediated by its established inhibitory effects on 11 beta-hydroxylation in the adrenal. These data are consistent with indications that corticosterone titer modulates female receptivity.

Adrenalectomy↗
PubMed1990

Metyrapone effects on beta-endorphin, ACTH and cortisol levels after chronic opiate receptor stimulation in man.

The aim of this study was to evaluate beta-endorphin, ACTH, and cortisol plasma levels during metyrapone administration in man after chronic opioid receptor stimulation. Metyrapone (750 mg every 4 hr for 6 doses) was administered to ten male heroin addicts, who had been on a maintenance therapy with methadone for at least 6 months and to ten healthy sex- and age-matched volunteers. Before metyrapone administration the basal levels of cortisol and ACTH were significantly decreased in addicts as compared to normal controls, while plasma beta-endorphin was not different. The response of beta-endorphin and ACTH to metyrapone administration was significantly blunted in addicts (p less than 0.01). These results suggest that the chronic stimulation of opiate receptors can impair the function of the anterior pituitary gland.

Adrenocorticotropic Hormone↗
PubMed1995

Determination of metyrapone and the enantiomers of its chiral metabolite metyrapol in human plasma and urine using coupled achiral-chiral liquid chromatography.

A coupled achiral-chiral liquid chromatographic assay has been developed to determine the concentrations of metyrapone and the enantiomers of its chiral metabolite metyrapol in plasma and urine. The chromatographic system consisted of a silica precolumn (75 x 4.6 mm I.D.) coupled in-line to a 250 x 4.6 mm I.D. column containing cellulose tris(4-methylbenzoate) coated on silica gel (Chiralcel OJ-CSP). When plasma samples were analyzed, the mobile phase was hexane-ethanol (92:8, v/v) modified with 0.1% diethylamine and when urine samples were analyzed the mobile phase was hexane-ethanol (94:6, v/v) modified with 0.2% diethylamine. Under these chromatographic conditions the chromatographic retentions [expressed as capacity factors (k')] for metyrapone were k' = 2.35 (plasma) and 2.52 (urine); for (-)-metyrapol k' = 4.22 (plasma) and 4.62 (urine); for (+)-metyrapone k' = 5.16 (plasma) and 5.86 (urine); enantioselectivities (alpha) were 1.09 (plasma) and 1.13 (urine). The assay has been validated for use in metabolic studies. The analyses of plasma and urine samples from one subject following oral administration of 750 mg of metyrapone indicated that the enzymatic reduction of myterapone by aldo-keto reductase was enantiospecific.

Chromatography, Liquid↗