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At least 163 records · Page 9Linked to original sources
PubMed2000

Effects of metyrapone administration on thyrotropin secretion in healthy subjects--a clinical research center study.

Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, 12 healthy subjects each underwent 2 studies, in random order: 1) each subject received an infusion of saline for 48 h; and 2) each subject received an infusion of saline and oral administration of metyrapone (500 mg every 4 h) for 48 h. Cortisol and TSH levels were measured every 15 min during the final 24 h of each study, and resulting mean hormone levels during the 24-h periods were compared between the two studies. Metyrapone administration reduced serum cortisol levels by 39% between 0800 and 1345 h and by 47% between 0200 and 0745 h, with no significant changes during other time periods. Metyrapone increased daytime (0800-1945 h) mean TSH levels by 35%, with no change in nocturnal (2000-0745 h) TSH levels. This led to equalization of daytime and nocturnal TSH levels and abolition of the usual circadian variation in TSH. TSH pulse frequency was no different between the two studies, whereas daytime TSH pulse amplitude increased 33% during metyrapone administration. There were no changes in TSH responses to TRH, or in serum T3 or free T4 levels, at the end of the studies. These results suggest that the early morning increase in endogenous cortisol levels in healthy subjects causes the daytime decrease in TSH levels. In addition, these results show that very mild changes in cortisol levels within the physiological range are sufficient to affect TSH secretion.

Adolescent↗
PubMed1989

Induction of cytochrome P-450c and P-450d by metyrapone in the primary culture of rat hepatocytes.

The effects of metyrapone on qualitative changes in cytochrome P-450-dependent drug metabolizing activities in primary cultures of rat hepatocytes were investigated. Metyrapone apparently increased benzo(a)pyrene hydroxylation and maintained both ethoxycoumarin-O-deethylation and propoxycoumarin-O-depropylation, whereas it had little effect on methoxycoumarin-O-demethylation. Furthermore, P-450d (high spin type of P-448) as well as P-450c (low spin type of P-448) were induced by metyrapone, while P-450b and P-450e were not. In conclusion, metyrapone act as a 3-methylcholanthrene-like inducer in the primary cultures of rat hepatocytes.

Animals↗
PubMed1983

In vitro inhibition of misonidazole toxicity and melphalan chemopotentiation by metyrapone.

Overnight exposure of Chinese hamster cells, V-79-753B, to 10(-3)M metyrapone protected them against the hypoxiamediated toxicity of 10(-2)M misonidazole. This protection was accompanied by an increase in radiation resistance. There was no appreciable change in the oxygen-enhancement ratio, nor in the amount of sensitisation produced by 10(-3)M misonidazole. Treatment of cells with metyrapone (10(-3)M) or dexamethasone (1 microgram ml-1 [approximately 2 X 10(-6)M]) prior to exposure first to 5 X 10(-3)M misonidazole in hypoxia and then to melphalan in air, substantially decreased the amount of chemopotentiation produced by the sensitiser, although the toxicity of melphalan alone was not affected in cells treated with either compound. Cells pretreated with either metyrapone or dexamethasone had 2-3 times more glutathione than control cells. This increase in GSH could not explain the change in radiation response, since cells pretreated with 5 X 10(-5)M flurbiprofen, a non-steroidal anti-inflammatory agent, had similarly high GSH levels, but their radiation response is similar to that of untreated cells (Millar et al, 1981). Neither dexamethasone nor flurbiprofen affected cell growth, whilst metyrapone markedly decreased the growth of cells. The results are discussed in terms of possible mechanism(s).

Animals↗
PubMed1983

[The discrepancy between ACTH and 11-deoxycortisol levels in a single dose metyrapone test].

Five healthy men were given 1.0 gr of metyrapone p.o. (MTP test) with and without 0.5 gr of 1- dopa p.o. (DOPA-MTP test) or 10 mg of metoclopramide p.o. (MTC-MTP test) and plasma 11-deoxycortisol, cortisol, ACTH and pregnenolone (only in MTP test) were determined before and hourly after the drug administrating for 6 hrs. In the MTP test, plasma 11-deoxycortisol increased significantly at 1 hr with peak at 5 hrs, whereas the significant increases of pregnenolone and ACTH were not seen until 2 hrs, although plasma cortisol levels were reduced definitely at 1 hr. Thus, the increase of 11-deoxycortisol in the MTP test should be divided into two phases; the increase in the phase II (later than 3 hrs) is due to pituitary ACTH reserve, and that in the phase I (until 2 hrs) is due to unknown mechanism other than pituitary reserve. In the DOPA-MTP test, the 11-deoxycortisol rise was significantly larger than that in the MTP test. The increases in 11-deoxycortisol at 4 hrs and 5 hrs in the MTC-MTP test were significantly smaller than those in the MTP test. The cortisol/(cortisol + 11-deoxycortisol) ratio reached its lowest point at 3 hrs in the MTP test and at 2 hrs (a 1 hr advance) in the DOPA-MTP and MTC-MTP tests. However, there were no significant differences in the responses of cortisol and ACTH to metyrapone in these tests. This provides evidence for a discrepancy between plasma 11-deoxycortisol and ACTH responses in a single dose metyrapone test, as disclosed by the simultaneous administration of dopamine agonist or antagonist with metyrapone.

17-Hydroxycorticosteroids↗
PubMedDate not supplied

The new highly sensitive adrenocorticotropin assay improves detection of patients with partial adrenocorticotropin deficiency in a short-term metyrapone test.

This study was designed to evaluate a short term metyrapone test using a highly sensitive (HS) IRMA ACTH assay and to evaluate the usefulness of a morning ACTH level as a screening test for partial ACTH deficiency. ACTH, 11-deoxycortisol and cortisol levels were evaluated over four hours in the morning after a single 40 mg/kg oral dose of metyrapone was administered at 0800 hours. 26 control children and 32 possibly pituitary deficient patients were evaluated. Based on 11-deoxycortisol levels alone, 17 of the patients passed the test, 11 patients failed the test and the result was inconclusive in four patients (12.5%). Evaluation of the increase in ACTH levels (delta ACTH) following metyrapone identified three of the above four with partial ACTH deficiency. The delta ACTH was consistent with the 11-deoxycortisol results in the remainder of patients. There was no difference in morning ACTH levels between controls and patients with partial ACTH deficiency. The measurement of ACTH using the HS IRMA assay, increases the sensitivity of the metyrapone test in detecting patients with partial ACTH deficiency. This test may be used safely in pediatric patients on a repetitive basis, especially in those children who may have progressive ACTH failure following hypothalamic-pituitary irradiation.

Adolescent↗
PubMed1983

Induction of hepatic cytochrome P-450 and drug metabolism by metyrapone in the rat: relevance to its effects in rat-liver cell culture.

The ability of metyrapone to induce hepatic cytochrome P-450 and xenobiotic metabolism in rats and rat hepatocyte culture has been studied. Metyrapone is a phenobarbitone-type inducer in rats. When rat hepatocytes were cultured with beta-naphthoflavone, a polycyclic hydrocarbon-type induction pattern was observed. In contrast, the observed induction pattern of both phenobarbitone and metyrapone in cell culture differed from that obtained with these compounds in vivo. The relationship between the nature of the induction of hepatic xenobiotic metabolism by metyrapone in vivo and its effects in liver-cell culture are discussed.

Animals↗
PubMed1975

Single-dose metyrapone test: review of a four-year experience.

Subnormal plasma 11-deoxycortisol (compound S) responses to metyrapone were found in patients with adrenal insufficiency or with Cushing syndrome caused by adrenal tumors and in those receiving long-term glucocorticoid or diphenylhydantoin sodium therapy. High normal or exaggerated responses were seen in women receiving oral contraceptives, patients with Cushing syndrome caused by adrenal hyperplasia, and those with untreated hypothyroidism. Diabetes mellitus, hypoglycemia, congestive failure, and obesity also were associated with exaggerated responses. Subnormal plasma S responses were observed in 15 patients who responded normally to a repeat test or to the standard metyrapone test. The abnormal response resulted from insufficient metyrapone, administration at the wrong time, or delay in obtaining the blood sample. The single-dose metyrapone test may be the procedure of choice in screening for adrenal insufficiency.

Adenoma, Chromophobe↗
PubMedDate not supplied

The urinary metabolic profile of metyrapone in the rat. Identification of two novel isomeric metyrapol N-oxide metabolites.

This study was designed to fully characterize the urinary metabolic profile of metyrapone following a 50 mg/kg ip dose to male Sprague-Dawley rats. Preliminary examination of alkaline dichloromethane extracts of urine by TLC and HPLC showed the absence of the intact drug, but the presence of moderate amounts of the two isomeric metyrapone mono-N-oxides, together with small amounts of metyrapol and the alpha-pyridone metabolite. These compounds have previously been reported as in vitro metabolites. Large amounts of two new metabolites of metyrapone were also observed and were conclusively identified as the isomeric metyrapol N-oxides by a combination of low- and high-resolution mass spectrometry. Quantitation by HPLC showed that metyrapol and the two metyrapone mono-N-oxides accounted for 4 and 10% of the dose, respectively. The two metyrapol mono-N-oxides accounted for more than 75% of the dose. These are novel metabolites not previously reported either as in vivo or in vitro metabolites.

Animals↗
PubMedDate not supplied

Circadian rhythm of urinary 17-hydroxycorticosteroids during metyrapone-induced ACTH release in normal subjects.

The circadian rhythm of urinary 17-OHCS was studied in nine normal subjects before and after oral metyrapone administration (750 mg every 4 hrs over a period of 24 hrs). The test was carried out twice in each subject with a shift of 12 hrs in the time of first administration (0800-test and 2000-test). For data from serial measurements of steroid metabolites on urine collected at 2-h intervals, the least squares fit of a 24-h cosine curve allowed the demonstration of a rhythm both in control conditions and during the 48-h span following metyrapone administration. Circadian acrophases were substantially similar. Total urinary 17-OHCS output in the first 24-h day following metyrapone was higher in the 2000-test as compared with the 0800-test (P less than .001). Conversely, in the second 24-h day, higher values were obtained in the 0800-test (P less than .025). The combined 48-h exretion, however, was identical in the two groups. The results suggest a time-limited action of metyrapone upon the pituitary-adrenal axis, since the increased excretion of 17-OHCS seems essentially accounted for by an exaggerated impulsive phase of ACTH secretion during the early morning hours.

17-Hydroxycorticosteroids↗
PubMed1990

Beta-lipotropin/adrenocorticotropic hormone responses to corticotropin releasing hormone, hypoglycemia, metyrapone and dexamethasone in normal human subjects.

1. The possible correlation between secretions of adrenocorticotropic hormone (ACTH) and of beta-lipotropin (beta-LPH), two pro-opiomelanocortin (POMC)-derived peptides, was investigated in 27 normal subjects under basal conditions (circadian rhythm), after the administration of 1 mg dexamethasone and in tests involving acute (human corticotropin releasing hormone, hCRH, and insulin tolerance test, ITT) and chronic (metyrapone) stimulation. 2. All subjects presented circadian rhythm and an operating negative feedback mechanism. Plasma ACTH and beta-LPH concentrations were correlated in all tests. The increase in ACTH and beta-LPH levels after hCRH was lower than that detected after ITT, though both increases were more discrete than those detected after stimulation with metyrapone. 3. The data suggest that, under hypoglycemic conditions, ACTH and beta-LPH secretion involves other POMC secretagogues in addition to endogenous CRH. The nature of these factors remains undefined. The greater efficacy of metyrapone treatment in elevating ACTH and beta-LPH levels is most likely mediated by sustained reduction in cortisol production and interruption of the rapid steroid feedback on the pituitary. 4. The molar peak ratios of the acute tests, which were similar to one another, differed from the peak ratio obtained during the metyrapone test, suggesting that corticotrophs may present pools with differentiated ACTH and beta-LPH content and release according to the type and/or duration of the stimulus.

Adrenocorticotropic Hormone↗
PubMed1990

Dexamethasone induction of gamma-glutamyl transferase in primary cultures of hepatocytes is enhanced by metyrapone.

Metyrapone, a cytochrome P-450 inhibitor, reduces by about 3,000 times the dexamethasone concentration required to cause a maximal induction of gamma-glutamyltransferase in adult rat hepatocyte cultures, in itself having no inducing activity. Metyrapone effect decreases as dexamethasone concentration approaches the optimally inducing one. Metyrapone action on low DEX concentrations is dose-dependent while inhibiting 7-ethoxycoumarin O-deethylation by 20% to 75%. At the same doses, metyrapone amplifies also the effects of all the hormonal concentrations inducing tyrosine aminotransferase. These phenomena may be triggered by a modulation of the glucocorticoid biotransformation effective at both transcriptional and translational levels.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Early morning hyperglycaemia "dawn phenomenon" in non-insulin dependent diabetes mellitus (NIDDM): effects of cortisol suppression by metyrapone.

To assess the effect of metyrapone on the early morning plasma glucose (PG) rise, seven NIDDM patients were studied from 2400 to 0900 h on two separate occasions one week apart. During the control study nights, patients received conventional therapy only (diet plus sulphonylurea) whereas on treatment nights, patients received in addition 30 mg/kg metyrapone orally at 2400 h. The plasma glucose (PG) levels from 0530 to 0900 h were significantly higher during the control night than the corresponding values following metyrapone. The control mean PG concentrations increased continuously from a nadir 8.4 +/- 1.1 mmol/l at 0400 h to a maximum of 9.4 +/- 1.1 mmol/l at 0800 h (p less than 0.01). In contrast following metyrapone administration a continuous decline in the PG concentration was noted from 2400 to 0800 h. The plasma glucose levels fell from 9.0 +/- 1.2 at 0400 h to 7.7 +/- 1.0 mmol/l at 0800 h (p less than 0.05). The mean overnight cortisol levels were 167.2 +/- 13.2 and 55.9 +/- 6.4 nmol/l (p less than 0.001) during the control and treatment studies, respectively. The cortisol levels were significantly higher during the control study at all time points from 0400 to 0900 h. No significant changes in insulin, C-peptide, glucagon, GH or catecholamine levels were observed between the two study periods. We conclude that the physiologic early morning rise in plasma cortisol possibly contributes to the pathogenesis of the dawn phenomenon in NIDDM patients.

Aged↗
PubMed1979

Metyrapone test with adrenocorticotrophic levels. Separating primary from secondary adrenal insufficiency.

Basal plasma adrenocorticotrophic hormone (ACTH) and cortisol concentrations as well as plasma ACTH and 11-deoxycortisol responses to the administration of a single dose of metyrapone were evaluated in 104 patients with intact pituitary-adrenal axis, in 20 patients with secondary adrenal insufficiency, and in seven patients with primary adrenal insufficiency. In patients with primary adrenal insufficiency, baseline ACTH levels were high. Following metyrapone administration, 11-deoxycortisol concentrations were low and ACTH levels did not change. In patients with secondary adrenal insufficiency, baseline plasma ACTH levels were normal, but neither 11-deoxycortisol nor ACTH levels increased in response to metyrapone. The metyrapone test is not only useful to screen for adrenal insufficiency, it is also useful to differentiate a primary from a secondary cause.

Adrenal Insufficiency↗
PubMedDate not supplied

Inhibition of antipyrine metabolite formation. Steady state studies with cimetidine and metyrapone in rats.

Antipyrine metabolite kinetics have been characterized in rats receiving an intravenous infusion of either saline, cimetidine, or metyrapone. 14CO2 exhalation rate-time profiles following [N-methyl-14C] antipyrine administration demonstrate that, when either cimetidine or metyrapone is maintained at a steady state plasma concentration, a constant degree of inhibition is evident. Under the conditions imposed in this in vivo study, the inhibitory potency of metyrapone is approximately 6 times that observed with cimetidine. Rate constants for the formation of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine have been calculated using breath and urinary metabolite data under the steady state inhibitory states. Metyrapone nonselectively inhibits the formation of all three oxidative metabolites by approximately one-third. Cimetidine inhibition is selective where rates of 3-methyl-hydroxylation and N-demethylation are reduced by 50% yet 4-hydroxylation is unaffected. The value of assessing inhibitory responses under steady state conditions is discussed and the nonlinear nature of the kinetics of inhibition, when a single bolus dose of inhibitor is used, is illustrated by means of computer simulation.

Animals↗
PubMedDate not supplied

Formation of two metyrapone N-oxides by rat liver microsomes.

In the presence of phenobarbital-pretreated rat liver microsomes and under oxidative conditions, metyrapone is transformed in vitro into reduced metyrapone and two other metabolites. In an effort to further characterize those metabolites, large-scale incubations of metyrapone were performed. Untransformed substrate and metabolites were extracted into chloroform under alkaline conditions and separated by thin-layer chromatography. The nature of the metabolites as N-oxides located on either pyridine ring was established by physical methodologies, mainly electron-impact and chemical-ionization mass spectrometry, and also by chemical reactions with titanous chloride. The formation of both N-oxides was increased in microsomes from phenobarbital-, but not from 3-methylcholanthrene-pretreated animals. N-Oxide formation during metyrapone metabolism might be an important step in its inhibitory action on the cytochrome P-450-mediated drug metabolism.

Animals↗
PubMed1978

Metyrapone-induced cardiovascular degenerative changes in non-arteriosclerotic and arteriosclerotic rats.

Virgin and breeder, male and female, Sprague-Dawley rats were unilaterally nephrectomized and given 1% saline drinking water. Animals were injected i.p., twice daily, with a 10 mg/100 g body wt dose of the 11-beta hydroxylation inhibitor, Metyrapone. After 7 weeks of treatment, both the previously nonarteriosclerotic virgin rats and the breeder rats with pre-existing arteriosclerosis developed de nove, widely distributed, intimal hyalinization of their peripheral arteries along with myocardial fibrosis and hyalinization of their intramyocardial coronary arteries. The Metyrapone-treated animals developed severe hypertension with greatly elevated serum creatin phosphokinase, glucose, BUN and cholesterol levels. The adrenal glands, hearts, and kidneys were greatly hypertrophied, in keeping with Metyrapone-induced extra ACTH release and the hypertension-induced myocardial and renal histopathology. Uniparous, Metyrapone-treated, female rats manifested an unusually high incidence of saccular aneurysms of the aorta. It is suggested that the hypertension and the intimal hyalinization and other specific morphologic characteristics of the cardiovascular degenerative changes observed were directly related to excess production of mineralocorticoids, e.g., deoxycorticosterone.

Adrenal Glands↗
PubMed1976

Association of the Ah locus with specific changes in metyrapone and ethylisocyanide binding to mouse liver microsomes.

The genetic trait of "responsiveness," which refers to the capacity for induction of cytochrome P-448 and numerous monooxygenase activities by certain aromatic hydrocarbons, is known to segregate almost exclusively as a single autosomal dominant gene among progeny of appropriate crosses originating from the responsive C57BL/6 and the nonresponsive DBA/2 inbred mouse strains. In this report the allele for responsiveness is shown to be associated with (a) increases in the apparent KS values for metyrapone bound to reduced P-450; (b) increases in the ethylisocyanide difference ratio (deltaA455-490/deltaA430-490);(c) increases in the deltaA455-490 per mg of microsomal protein but not in the deltaA430-490 per mg of protein from the reduced P-450-ethylisocyanide complex; (d) an approximately 2-nm hypsochromic shift in the spectral maximum in the 446 nm region for the reduced P-450-metyrapone complex; (e) an approximately 2-nm hypsochromic shift of the absorption maximum in the 455 nm region, but not of the maximum in the 430 nm region, for the reduced P-450-ethylisocyanide complex; and (f) larger increases in the deltaA455-490 than in the deltaA430-490 per mg of microsomal protein for the reduced P450-ethylisocyanide complex as a function of increasing pH. All of these phenomena are felt to be associated with the genetically regulated induction of liver microsomal cytochrome P-448 by polycyclic aromatic compounds. Whereas increases in the total hepatic P-450 content appear to be expressed almost exclusively as a single autosomal dominant trait, the increase in apparent KS value for metyrapone bound to reduced P-450 appears to be expressed additively. The reason for this finding is unclear. The increase in apparent KS value for metyrapone in 3-methylcholanthrene-treated rats is known to occur even when the induction process is presumably blocked by treating the rat concomitantly with cycloheximide. Several lines of evidence in this report indicate that, although total P-450 content does not increase in C57BL/6N mice treated with 3-methylcholanthrene plus cycloheximide, hepatic P-448 induction does occur; P-448 induction does not occur in DBA/2N mice under these same conditions. These results indicate that cytochrome P-448 induction is relatively resistant to the inhibition of protein synthesis and that a responsive animal treated with 3-methylcholanthrene plus cycloheximide cannot be considered experimentally the same as a genetically nonresponsive animal treated with 3-methylcholanthrene alone.

Animals↗
PubMed1993

Use of metyrapone to treat pituitary-dependent hyperadrenocorticism in a cat with large cutaneous wounds.

Metyrapone, a drug that inhibits cortisol production, was used to lower plasma cortisol concentration and alleviate skin lesions caused by pituitary-dependent hyper-adrenocorticism in a cat. Plasma cortisol concentration was documented by ACTH stimulation test results. During metyrapone treatment, alopecia, thin skin, and large cutaneous wounds resolved. Metyrapone was administered orally at a dosage of 65 mg/kg of body weight, every 12 hours. Metyrapone may be used in conjunction with surgery in the management of pituitary-dependent hyperadrenocorticism in cats.

Adrenalectomy↗