Polymorphically acetylated aminoglutethimide in humans

Coombes, R. Charles; Foster, A.; Harland, S. J.; Jarman, Michael; Nice, E.C.

doi:10.1038/bjc.1982.209

Cited by 26 publications

(9 citation statements)

References 8 publications

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“…There is no evidence that it is inducible. Coombes et al (1982) showed that in subjects acetylator-phenotyped into fast and slow acetylators using sulphadimidine, the slow acetylators excreted more AG (mean 28% in 24 h) of a single dose than did fast acetylators (12%) but the latter excreted more acetylAG (8.8%) than the former (3.9%). These observations have thus been confirmed by the present study.…”

Section: Resultsmentioning

confidence: 99%

“…Some form of product inhibition is a possibility, although this would have to be one of regulation of an oxidative pathway(s) by acetyl metabolites). Coombes et al (1982) showed that slow acetylators excreted more nitroglutethimide in the urine than fast acetylators but since even in the former this constituted only 0.1% of the dose, it is unlikely to make a major contribution to AG disposition. Deacetylation of mono-and diacetyldapsone has been documented in man (Gelber et al, 1971) and in the case of that drug rapidly achieves equilibrium.…”

Section: Resultsmentioning

confidence: 99%

“…The residue was taken up in 250 ,ul of solvent system (methanol/water v/v 42:58) and 50 RI injected into the chromatograph. The solvent was delivered at 1 ml/min to a 25 cm x 4.6 mm ,u Bondapak C18 column of 10 pm particle size (Waters Associates, (Baker et al, 1981;Coombes et al, 1982). The interassay coefficients of variation (n = 6) for AG in plasma ranged from 14.3% at 1 pLg/ml to 6.9% at 8 ,ug/ml and in urine from 3.7% at 10 ,ug/ml to 1.9% at 160 S.g/ml.…”

Section: Acetylator Phenotypingmentioning

confidence: 99%

“…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). Other metabolites that have been demonstrated are N-formyl-aminoglutethimide, nitroglutethimide and N-hydroxylaminoglutethimide (Baker et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Acetylator Phenotypingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The effect of acetylator phenotype on the disposition of aminoglutethimide.

Adam¹,

Rogers²,

Amiel³

et al. 1984

Brit J Clinical Pharma

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“…A new metabolite, N-hydroxyl-AG, can be detected in the urine after enzyme induction (38). AG is also metabolised by a non-induced pathway-acetylation (39). Slow acetylators produce lesser amounts of N-acetyl-AG.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

Could aminoglutethimide replace adrenalectomy?

Harris

1985

Breast Cancer Res Tr

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Could aminoglutethimide replace adrenalectomy? This question has already been answered in clinical practice in the United Kingdom, for surgical adrenalectomy has declined markedly in frequency as new hormonal therapy has appeared. An optimal assessment of an endocrine therapy can only be made in previously untreated patients because of the heterogeneity of previously treated populations. Thus aminoglutethimide (AG) and adrenalectomy have been compared for previously untreated and treated populations. Because AG is commonly called 'medical adrenalectomy', this article will review and compare aminoglutethimide therapy with surgical adrenalectomy and make the case that surgical adrenalectomy is no longer indicated in the management of breast cancer.

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Additive hormonal therapy in women with advanced breast cancer

Ingle

1984

Cancer

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A great deal of work has been done over the last decade in the assessment of additive hormonal treatment approaches in women with advanced breast cancer. This work has been prompted by a number of factors which include: (1) the introduction of new hormonal agents, (2) increased knowledge of the physiologic actions of several hormonal agents, (3) the development of hormonal receptor assays to better predict the probability of hormonal responsiveness in a given patient, and (4) the apparent plateau in efficacy of cytotoxic chemotherapeutic approaches. The hormonal agents that have been studied most extensively in the recent past include tamoxifen (an antiestrogen), aminoglutethimide (an aromatase inhibitor), and medroxyprogesterone acetate (a progestin). In postmenopausal women, several agents exist that appear about equal in efficacy; but, currently, tamoxifen appears to be preferred as the initial hormonal treatment, primarily because of its low incidence of side effects. Studies involving combination hormonal therapy have produced interesting results, but further work is needed to establish superiority over tamoxifen alone. In premenopausal women, tamoxifen does have antitumor activity in some patients but has not been established as a replacement for oophorectomy. Properly conducted comparative trials will remain essential for the determination of the proper place of newer hormonal therapy approaches in clinical practice.

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Polymorphically acetylated aminoglutethimide in humans

Cited by 26 publications

References 8 publications

The effect of acetylator phenotype on the disposition of aminoglutethimide.

The effect of acetylator phenotype on the disposition of aminoglutethimide.

Could aminoglutethimide replace adrenalectomy?

Additive hormonal therapy in women with advanced breast cancer

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