Aminoglutethimide

Source: Wikipedia, the free encyclopedia.

Aminoglutethimide
Clinical data
Trade namesElipten, Cytadren, Orimeten, numerous others
Other namesAG; AGI; Ba 16038; Ciba 16038; ND-1966; 2-(p-Aminophenyl)-2-ethylglutarimide
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa604039
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
Drug classAromatase inhibitor; Antiestrogen; Steroidogenesis inhibitor; Antiglucocorticoid
ATC code
Pharmacokinetic data
BioavailabilityRapid, complete[1]
MetabolismLiver (minimal; acetylation)[1]
Elimination half-life12.5 hours[1]
ExcretionUrine (34–54%, unchanged)[1]
Identifiers
  • (RS)-3-(4-aminophenyl)-3-ethyl-piperidine-2,6-dione
JSmol)
ChiralityRacemic mixture
  • O=C1NC(=O)CCC1(c2ccc(N)cc2)CC
  • InChI=1S/C13H16N2O2/c1-2-13(8-7-11(16)15-12(13)17)9-3-5-10(14)6-4-9/h3-6H,2,7-8,14H2,1H3,(H,15,16,17) checkY
  • Key:ROBVIMPUHSLWNV-UHFFFAOYSA-N checkY
  (verify)

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of

performance- and physique-enhancing purposes.[7][1] AG is taken by mouth three or four times per day.[8][4]

corticosteroid synthesis inhibitor.[9][10][11][6][7]

AG was introduced for medical use, as an anticonvulsant, in 1960.[12][13] It was withdrawn in 1966 due to toxicity.[12][13] Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the treatment of Cushing's syndrome, breast cancer, and prostate cancer from 1969 and thereafter.[9][13][6] However, although used in the past, it has mostly been superseded by newer agents with better efficacy and lower toxicity such as ketoconazole, abiraterone acetate, and other aromatase inhibitors.[4][9] It remains marketed only in a few countries.[14][7]

Medical uses

AG is used as an anticonvulsant in the treatment of

tumor regression.[6] In any case, AG is not recommended as a first-line therapy in prostate cancer, but instead only as a second-line therapy.[6][17] It has only rarely been used in the treatment of prostate cancer.[4]

AG is used for adrenal steroidogenesis inhibition

serum glutamic-oxaloacetic transaminase, alkaline phosphatase, and bilirubin.[1][8]

tumor regression and is moderately less toxic in comparison.[4] AG can still be a useful alternative in those who have failed or are unable to tolerate ketoconazole and other therapies however.[4]

Available forms

AG is provided most commonly in the form of 250 mg tablets.[7][8]

Non-medical uses

AG is used by

water retention, and fat gain.[7]

Contraindications

AG should not be used in people with known

chicken pox, shingles (herpes zoster), infection, kidney disease, liver disease, and hypothyroidism.[1]

Side effects

AG has many

white blood cell count, platelets, or both, occurs rarely, with an incidence of about 0.9%.[6][18] It is usually seen within the first 7 weeks of treatment and resolves within 3 weeks following discontinuation.[6] AG is discontinued in 5 to 10% of people due to intolerable side effects.[6] The central nervous system side effects of AG are due to its nature as an anticonvulsant and relation to glutethimide.[17]

Overdose

In the event of

absorption and dialysis to enhance elimination.[21]

Interactions

AG has an interaction with all corticosteroids.[1] It enhances the metabolism of dexamethasone, so hydrocortisone should be used instead.[8] If the person is taking warfarin, the dosage of warfarin may need to be increased.[8] Alcohol potentiates the central nervous system side effects of AG.[8] Dosages of theophylline, digitoxin, and medroxyprogesterone acetate may need to be increased.[8]

Pharmacology

Pharmacodynamics

AG is a

competitive inhibitor of multiple steroidogenic enzymes, including:[9][10][11][6][7]

As such, AG is an

adrenal androgens, AG has been shown to significantly suppress dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone levels in men.[6] Although it is most potent in inhibiting aromatase among the enzymes it targets, AG is described nonetheless as a relatively weak aromatase inhibitor.[11][4] In addition, it is described as a much more potent aromatase inhibitor than adrenal steroidogenesis inhibitor.[17] AG can inhibit aromatase by 74 to 92% and decrease circulating estradiol levels by 58 to 76% in men and postmenopausal women.[1][7] AG is not an effective ovarian steroidogenesis inhibitor in premenopausal women.[17] However, interference with ovarian steroidogenesis by AG may in any case result in hyperandrogenism and virilization in premenopausal women.[8][7]

Pharmacodynamics of aromatase inhibitors
Generation Medication Dosage % inhibitiona Classb IC50c
First Testolactone 250 mg 4x/day p.o. ? Type I ?
100 mg 3x/week i.m. ?
Rogletimide 200 mg 2x/day p.o.
400 mg 2x/day p.o.
800 mg 2x/day p.o.		 50.6%
63.5%
73.8%		 Type II ?
Aminoglutethimide 250 mg mg 4x/day p.o. 90.6% Type II 4,500 nM
Second Formestane 125 mg 1x/day p.o.
125 mg 2x/day p.o.
250 mg 1x/day p.o.		 72.3%
70.0%
57.3%		 Type I 30 nM
250 mg 1x/2 weeks i.m.
500 mg 1x/2 weeks i.m.
500 mg 1x/1 week i.m.		 84.8%
91.9%
92.5%
Fadrozole 1 mg 1x/day p.o.
2 mg 2x/day p.o.		 82.4%
92.6%		 Type II ?
Third Exemestane 25 mg 1x/day p.o. 97.9% Type I 15 nM
Anastrozole 1 mg 1x/day p.o.
10 mg 1x/day p.o.		 96.7–97.3%
98.1%		 Type II 10 nM
Letrozole 0.5 mg 1x/day p.o.
2.5 mg 1x/day p.o.		 98.4%
98.9%–>99.1%		 Type II 2.5 nM
Footnotes: a = In
homogenates
. Sources: See template.

Pharmacokinetics

With

absorption of AG is rapid and complete.[1] It is well-distributed throughout the body.[1] In terms of metabolism, a portion of AG is acetylated in the liver.[1] The biological half-life of AG is 12.5 hours.[1] It is excreted in urine 34 to 54% unchanged.[1]

Chemistry

AG is a

derivative of glutethimide.[3][12][7] It is also known by its chemical names 2-(4-aminophenyl)-2-ethylglutarimide and 2-(aminophenyl)-3-ethylpiperidine-2,6-dione.[26][7] Aside from glutethimide, AG is structurally related to rogletimide (pyridoglutethimide) and thalidomide, as well as amphenone B, metyrapone, and mitotane.[10][27][28][29][12]

History

AG was introduced for medical use, as an anticonvulsant, in 1960.[12][13] In 1963, it was reported that AG had induced symptoms of Addison's disease (adrenal insufficiency) in a young girl.[12] Following additional reports, it was determined that AG acts as a steroidogenesis inhibitor.[12] As such, the discovery of AG as a steroidogenesis inhibitor was serendipitous.[9] The medication was withdrawn from the market in 1966 due to its adverse effects.[12][13] The first report of AG in the treatment of breast cancer was published in 1969, and the first report of AG in the treatment of prostate cancer was published in 1974.[13][6] The medication was one of the first adrenal steroidogenesis inhibitors as well as the first aromatase inhibitor to be discovered and used clinically, and led to the development of other aromatase inhibitors.[18][4][30][9] Along with testolactone, it is described as a "first-generation" aromatase inhibitor.[7] AG has largely been superseded by medications with better effectiveness and tolerability and reduced toxicity, such as ketoconazole, abiraterone acetate, and other aromatase inhibitors.[4][6][9]

Society and culture

Generic names

Aminoglutethimide is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name, while aminoglutéthimide is its DCFTooltip Dénomination Commune Française and aminoglutetimide is its DCITTooltip Denominazione Comune Italiana.[14][26][31][3] It is also known by its developmental code names Ba 16038, Ciba 16038, and ND-1966.[14][26][31][3]

Brand names

AG has been marketed under brand names including Elipten, Cytandren, and Orimeten.[26][31][7][14][3] It has also been marketed under other brand names such as Aminoblastin, Rodazol, and Mamomit, among numerous others.[31][7]

Availability

AG appears to remain marketed only in a few countries, which include China, Egypt, and Lithuania.[14] Previously, AG was available very widely throughout the world, including in more than two dozen countries and under numerous brand names.[7] Among other places, it was marketed in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, South America, Israel, Malaysia, and Hong Kong.[31][7]

References

  1. ^
    ISBN 978-0-8036-4070-2
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  2. ISBN 978-1-351-78989-9
    .
  3. ^
    ISBN 978-94-011-4439-1
    .
  4. ^
    ISBN 978-1-60327-829-4
    .
  5. PMID 17961023
    .
  6. ^
    ISBN 978-1-4613-1731-9
    .
  7. ^
    ISBN 978-0-9828280-1-4
    .
  8. ^
    ISBN 978-1-284-05374-6
    .
  9. ^
    ISBN 978-0-19-969739-7
    .
  10. ^
    ISBN 978-0-203-30415-0
    .
  11. ^
    ISBN 978-1-4200-4744-8
    .
  12. ^
    ISBN 978-0-471-89979-2
    .
  13. ^
    ISBN 978-1-4613-3837-6
    .
  14. ^ a b c d e "List of Aromatase inhibitors". Drugs.com.
  15. ISBN 978-94-015-7190-6
    .
  16. ISBN 978-3-642-81659-8
    .
  17. ^
    ISBN 978-1-4471-1686-8
    .
  18. ^
    ISBN 978-94-009-0709-6
    .
  19. ^
    ISBN 978-1-86395-174-6
    .
  20. ISBN 9780874349979
    .
  21. ISBN 978-1-56363-429-1
    .
  22. PMID 17602675
    .
  23. ISBN 978-0-12-809842-4
    .
  24. ISBN 978-1-4684-5036-1
    .
  25. ISBN 978-3-642-96720-7
    .
  26. ^
    ISBN 978-1-4757-2085-3
    .
  27. ISBN 978-3-527-31247-4
    .
  28. ISBN 978-0-521-22673-8
    .
  29. ISBN 978-1-4831-9221-5
    .
  30. ISBN 978-3-7643-8693-1
    .
  31. ^
    ISBN 978-3-88763-075-1
    .
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