Effects of Amino-glutethimide on Adrenal Function in Man<sup>1</sup>

Fishman, Lawrence M.; Liddle, Grant W.; Island, Donald P.; Fleischer, Norman; Kuchel, O

doi:10.1210/jcem-27-4-481

Cited by 157 publications

(45 citation statements)

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“…It inhibits peripheral tissues containing aromatase and in both adrenal steroid synthesis (Cash et al, the breast carcinoma itself. 1967;Fishman et al, 1967) effects, details of its metabolism remain obscure. Older studies (Douglas & Nicholls, 1972) have indicated that N-acetylation to acetamidoglutethimide (acetylAG) is a major (4-25%) pathway and more recent studies suggested that this acetylation is polymorphic (Coombes et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

The effect of acetylator phenotype on the disposition of aminoglutethimide.

Adam¹,

Rogers²,

Amiel³

et al. 1984

Brit J Clinical Pharma

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1 Aminoglutethimide (AG) 500 mg was administered orally to four normal volunteers and eight patients undergoing treatment for metastatic breast cancer. In each subject the acetylator phenotype was established from the monoacetyldapsone (MADDS)/dapsone (DDS) ratio. 2 Acetylaminoglutethimide (acetylAG) rapidly appeared in the plasma and its disposition paralleled that of AG. 3 A close relationship (P < 0.01) was observed between the acetyl AG/AG and MADDS/DDS ratio suggesting that AG may undergo polymorphic acetylation like DDS. 4 AG half-life was 19.5 + 7.7 h in seven fast acetylators of DDS and 12.6 + 2.3 h in five slow acetylators and its apparent metabolic clearance was significantly (P < 0.01) related to the acetylAG/AG ratio. 5 Over 48 h the fast acetylators excreted 7.7 + 4.4% of the administered AG dose in the urine as unchanged AG as compared to 12.4 + 2.8% in slow acetylators. A much smaller fraction of the dose was excreted as acetylAG: 3.6 + 1.5% by fast and 1.9 ± 1.0% by slow acetylators respectively. 6 After 7 days treatment with AG at an accepted clinical dose regimen to the eight patients there were significant reductions in the half-lives of AG (P < 0.01) and acetylAG (P < 0.01) and a trend (0.1 > P > 0.05) towards reduction of the acetylAG/ AG ratio which became significant (P < 0.05) if the one patient on a known enzyme inducer was omitted. The mean apparent volume of distribution was not significantly (P > 0.1) altered but the mean apparent systemic clearance of AG was increased (P < 0.05). These changes are attributed to auto-induction of oxidative enzymes involved in AG metabolism.

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Section: Introductionmentioning

confidence: 99%

The effect of acetylator phenotype on the disposition of aminoglutethimide.

Adam¹,

Rogers²,

Amiel³

et al. 1984

Brit J Clinical Pharma

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“…AG blocks formation of pregnenolone in the steroid synthetic pathway by inhibiting 20.22 desmolase (12,13). As shown in Table I Effect ofsteroid status on ion transport.…”

Section: Resultsmentioning

confidence: 99%

“…The lack of aldosterone suppression was unexpected because similar doses administered to rats and man effectively inhibited aldosterone output (13,(35)(36)(37). 4 Administration of pharmacologic doses of MIP in vivo increased net Na absorption, PD, ISC and J'", when these parameters were subsequently determined in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Epinephrine, however, stimulates salt and water absorption in the intestine (14,31), and, therefore would be expected to cause an effect opposite of that observed. (d) AG, like the closely related sedative glutethimide, can cause hyperplasia of hepatic smooth endoplasmic reticulum after chronic administration (32), causing accelerated metabolism of glucocorticoids (13), androgens (33), and aminoglutethimide itself (34 (27). cyclic nucleotide in rabbits treated with either NIP or AG, and this may account for the differences between our study and these prior in vitro observations in the rat.…”

Section: Discussionmentioning

confidence: 99%

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Physiologic and Pharmacologic Effects of Glucocorticoids on Ion Transport across Rabbit Ileal Mucosa In Vitro

Sellin¹,

Field²

1981

J. Clin. Invest.

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“…In the adrenals, it inhibits 20,22-desmolase, ll#-hydroxylase, 18-hydroxylase and possibly 21-hydroxylase (Cohen 1968; Dexter et al, J967; Kahnt & Neher, 1966;Sheppard et al, 1966). Although a compensatory increase in ACTH secretion (Fishman et al, 1967) causes a sustained output of most steroids (Harris et al, 1983;Vermeulen et al, 1983), the adrenal glucocorticoid response may be inadequate in certain circumstances, and glucocorticoid, and sometimes mineralocorticoid, replacement therapy are therefore recommended. Androstenedione (the one hormone for which a depression might be beneficial) is sustained or elevated unless the patient is given concommitant glucocorticoid therapy (Samojlik & Santen, 1978).…”

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confidence: 99%