255. Dual sites of metyrapone inhibition: correlation of in vivo and in vitro studies

Carballeira, Andrés; Jacobi, Jorge D.; Fishman, Lawrence M.; Cheng, Shi

doi:10.1016/0022-4731(74)90400-2

Cited by 9 publications

(11 citation statements)

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“…This compound can also interfere with cortisol formation by inhibiting the cholesterol side chain cleavage complex (522) and, to a lesser extent, 17␣-hydroxylase and 18-hydroxylase activity (523). In clinical practice, metyrapone is administered orally at a dosage ranging from 500 to 6000 mg/d; it has a rapid action, but the short half-life (1.9 Ϯ 0.7 h) means multiple daily dosing, generally four times, and up to six times a day (524).…”

Section: Metyraponementioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

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Section: Metyraponementioning

confidence: 99%

The Treatment of Cushing's Disease

et al. 2015

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“…The eluate from the cortolones area was divided into two portions after being counted. Twenty milligrams of /?-cortolone 1 The following trivial names have been used for steroid hormone metabolites: tetrahydrocortisone (THE), 3a,-17,21-trihydroxy-pregnane-ll,20-dione; tetrahydrocortisol (THF), 3a ) ll/? ) 17,21-tetrahydroxypregnan-20-one; allotetrahydrocortisol (ATHF), 3a,ll/?,17,21-tetrahydroxy5a-pregnan-20-one; cortols, pregnane-3a,ll/?,17,20a,21-pentol and pregnane-3a,ll/?,17,20/6,21-pentol; cortolones, cortolone and /?-cortolone; cortolone, 3a,17,20a,21-tetrahydroxypregnan-11-one; /?-cortolone, 3a,17,20/3,21-tetrahydroxypregnan-11-one; Reichstein's substance U (R-U), 17,20/?, 21 -trihydroxy -A 4 -pregnene -3,11-dione; Reichstein's substance epi-U (R-epi-U), 17,20a,21-trihydroxy-A 4 -pregnene-3,11-dione.…”

Section: Radioactive Urinary Cortisol Metabolitesmentioning

confidence: 99%

“…M ETYRAPONE has been shown to interfere with the biosynthesis of cortisol in the adrenal gland by inhibiting both a very early step, cleavage of 20,22-dihydroxycholesterol to form pregnenolone (1), and the final step, 11/3-hydroxylation of 11-deoxycortisol (2). The extraadrenal effects of the drug have been studied and the reports indicate that it produces changes in the plasma disappearance rate, apparent distribution volume (DV), and MCR of cortisol (3)(4)(5)(6).…”

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confidence: 97%

Extraadrenal Effects of Metyrapone in Man*

Levin

Zumoff

Fukushima

1978

The Journal of Clinical Endocrinology & Metabolism

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[14C]Cortisol was injected iv into three subjects during a control period and while receiving metyrapone. The plasma kinetics of the tracer cortisol and the patterns of its urinary metabolites were measured. Metyrapone caused an increase in the volume of distribution of cortisol (34%) and in the MCR (75%); the half-life was decreased by 25%. There were marked changes in the urinary metabolite pattern: 3 alpha,11 beta,17,21-tetrahydroxy-5 alpha-pregnan-20-one, 3 alpha,17,21-trihydroxy-pregnane-11,20-dione(THE), pregnane-3 alpha,11 beta,17,20 alpha,21-pentol, plus pregnane-3 alpha,11 beta,17,20 beta-21-pentol (cortol), and 3 alpha,17,20 alpha,21-tetrahydroxypregnan-11-one (cortolone) all decreased by an average of 62%, 44%, 38%, 45%, and 25% respectively. In contrast, there was an increase of 296% in 3 alpha,17,20 beta,21-tetrahydroxypregnan-11-one (beta-cortolone). To account for these effects it is postulated that metyrapone has the following extraadrenal actions: 1) it inhibits the back reduction of cortisone to cortisol and 2) it stimulates the 20-ketosteroid reductase that converts THE to beta-cortolone.

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“…It has been previously demonstrated that metyrapone inhibits the mitochondrial enzymes for cholesterol cleavage (25,26), 19-hydroxylase (17, 26), and 11/?-and 18-hydroxylase (2,4). We have now added in vivo evidence for an additional mitochondrial cytochrome P-450-dependent step inhibited by metyrapone.…”

Section: Discussionmentioning

confidence: 97%

Parallelism of 11β- and 18-Hydroxylation Demonstrated by Urinary Free Hormones in Man*

Sonino

Levine

Vecsei

et al. 1980

The Journal of Clinical Endocrinology & Metabolism

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To investigate whether the functions of 11 beta- and 18-hydroxylase are parallel in the human adrenal cortex, we measured urinary free deoxycorticosterone (DOC), free 18-hydroxy-DOC (18-OH-DOC), and free corticosterone (B) in 22 subjects (aged 3 6/12 to 19 yr) before and after metyrapone administration and ACTH infusion. The substrate to product ratio was used as an index of enzyme activity. There were parallel changes in the ratios of DOC to B (11 beta-hydroxylase) and DOC to 18-OH-DOC (18-hydroxylase) in all conditions, while the B to 18-OH-DOC ratio (product ratio) was relatively constant. The correlations between the ratios of DOC to B and DOC to 18-OH-DOC as well as between B and 18-OH-DOC were highly significant under all conditions (r = 0.89; P = 0.00001). These findings are consistent with previous in vitro studies and studies in patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, suggesting that a single enzyme system is responsible for both 11 beta- and 18-hydroxylation of DOC in the adrenal zona fasciculata. As part of the metyrapone study, 18-OH-B was measured: 18-OH-B values decreased significantly, and the B to 18-OH-B ratio increased during metyrapone administration (from 0.38 +/- 0.09 to 1.79 +/- 0.04; P < 0.005), showing inhibition of 18-hydroxylation of B as well. Since 18-OH-B was suppressed without a decrease in PRA, we concluded that this inhibition is a primary metyrapone effect and not the result of increased DOC and suppressed PRA.

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255. Dual sites of metyrapone inhibition: correlation of in vivo and in vitro studies

Cited by 9 publications

References 0 publications

The Treatment of Cushing's Disease

The Treatment of Cushing's Disease

Extraadrenal Effects of Metyrapone in Man*

Parallelism of 11β- and 18-Hydroxylation Demonstrated by Urinary Free Hormones in Man*

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