 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Elipten, Cytadren, Orimeten, numerous others |
| Other names | AG; AGI; Ba 16038; Ciba 16038; ND-1966; 2-(p-Aminophenyl)-2-ethylglutarimide |
| AHFS/Drugs.com | Consumer Drug Information |
| MedlinePlus | a604039 |
| Pregnancy category |
|
| Routes of administration | By mouth |
| Drug class | Aromatase inhibitor;Antiestrogen;Steroidogenesis inhibitor;Antiglucocorticoid |
| ATC code | |
| Pharmacokinetic data | |
| Bioavailability | Rapid, complete[1] |
| Metabolism | Liver (minimal;acetylation)[1] |
| Eliminationhalf-life | 12.5 hours[1] |
| Excretion | Urine (34–54%, unchanged)[1] |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.004.325 |
| Chemical and physical data | |
| Formula | C13H16N2O2 |
| Molar mass | 232.283 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
| |
| |
| (verify) | |
Aminoglutethimide (AG), sold under the brand namesElipten,Cytadren, andOrimeten among others, is a medication which has been used in the treatment ofseizures,Cushing's syndrome,breast cancer, andprostate cancer, among other indications.[2][3][4][5][6][7] It has also been used bybodybuilders,athletes, and other men formuscle-building andperformance- and physique-enhancing purposes.[7][1] AG is takenby mouth three or four times per day.[8][4]
Side effects of AG includelethargy,somnolence,dizziness,headache,appetite loss,skin rash,hypertension,liver damage, andadrenal insufficiency, among others.[4] AG is both ananticonvulsant and asteroidogenesis inhibitor.[3][4] In terms of the latter property, itinhibitsenzymes such ascholesterol side-chain cleavage enzyme (CYP11A1, P450scc) andaromatase (CYP19A1), thereby inhibiting the conversion ofcholesterol intosteroid hormones and blocking theproduction ofandrogens,estrogens, andglucocorticoids, among otherendogenoussteroids.[4] As such, AG is anaromatase inhibitor andadrenal steroidogenesis inhibitor, including both anandrogen synthesis inhibitor and acorticosteroid 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AG was introduced for medical use, as an anticonvulsant, in 1960.[12][13] It was withdrawn in 1966 due totoxicity.[12][13] Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the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 betterefficacy and lower toxicity such asketoconazole,abiraterone acetate, and other aromatase inhibitors.[4][9] It remains marketed only in a few countries.[14][7]
AG is used as an anticonvulsant in the treatment ofpetit mal epilepsy and as a steroidogenesis inhibitor in the treatment of Cushing's syndrome,postmenopausal breast cancer, and prostate cancer.[15][6][12][7] It is also used to treatsecondary hyperaldosteronism,edema,adrenocortical carcinoma, andectopicadrenocorticotropic hormone (ACTH) producingtumors.[3][1][16] When used as a steroidogenesis inhibitor to treat breast cancer and prostate cancer, AG is given in combination withhydrocortisone,prednisone, or an equivalentcorticosteroid to preventadrenal insufficiency.[4][6] AG is a second- or third-line choice in the treatment ofhormone-sensitivemetastatic breast cancer. While effective in the treatment of breast cancer in postmenopausal women, it is not effective inpremenopausal women and is not an effectiveovarian steroidogenesis inhibitor, probably because it is not apotent enougharomatase inhibitor.[6][17] The medication is effective in the treatment of prostate cancer, but its effectiveness is low and inconsistent, likely due to its relatively weak steroidogenesis inhibition and poorpharmacokinetics.[6] Nonetheless, AG was found to be non-significantly different in effectiveness fromsurgical adrenalectomy in terms of prostate cancertumor 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 inhibitionby mouth at a dosage of 250 mg three times per day (750 mg/day total) for the first 3 weeks of therapy and then increased to 250 mg four times per day (1,000 mg/day total) thereafter.[4] It can be used at a dosage of up to 500 mg four times per day (2,000 mg/day).[1][8] It is used as anaromatase inhibitor to inhibitperipheral estrogen production by mouth at a dosage of 125 mg twice per day (250 mg/day total), without significant suppression of adrenal steroidogenesis at this dosage.[17] Maximal aromatase inhibition is said to occur between dosages of 250 to 500 mg per day.[7] The side effects of AG are less frequent and severe at this dosage.[17] However, they are still less when AG is combined with hydrocortisone, and so AG is generally combined with a corticosteroid even at this lower dosage.[17] AG should only be used under closemedical supervision and withlaboratory tests includingthyroid function,baseline hematological,serum glutamic-oxaloacetic transaminase,alkaline phosphatase, andbilirubin.[1][8]
Ketoconazole can achieve similar decreases in steroid hormone levels as AG but is more effective in promotingtumor regression and is moderately less toxic in comparison.[4] AG can still be a useful alternative in those who have failed or are unable totolerate ketoconazole and other therapies however.[4]
AG is provided most commonly in the form of 250 mgtablets.[7][8]
AG is used bybodybuilders,athletes, and other men to lower circulating levels ofcortisol in the body and thereby preventmuscle loss.[7][1] Cortisol iscatabolic toprotein inmuscle and effective suppression of cortisol by AG at high doses can prevent muscle loss.[7] It is usually used in combination with ananabolic steroid to avoidandrogen deficiency.[7] However, the usefulness of AG for such purposes has been questioned, with few users reportedly having positive comments about it, and the risks of AG are said to be high.[7][1] In any case, AG is also used by bodybuilders and other men for its actions as an aromatase inhibitor in order to decrease estrogen levels.[7] It is said to be useful for inhibiting the estrogenic side effects of certain anabolic steroids such asgynecomastia, increasedwater retention, andfat gain.[7]
AG should not be used in people with knownhypersensitivity to AG.[1] It should not be used in women who arepregnant orbreastfeeding.[1] Other potential contraindications includechicken pox,shingles (herpes zoster),infection,kidney disease,liver disease, andhypothyroidism.[1]
AG has manyside effects and is a relativelytoxic medication, although its side effects are described as usually relatively mild.[4][6] The side effects of AG includelethargy,fatigue,weakness,malaise,drowsiness,somnolence,depression,apathy,sleep disturbances,stomach discomfort,nausea,vomiting,ataxia,joint aches and pains,fever,skin rash,hypotension orhypertension,high cholesterol levels,virilization,hypothyroidism,thyroid abnormalities,elevated liver enzymes,jaundice,hepatotoxicity,weight gain,leg cramps,personality changes,blood dyscrasias, andadrenal insufficiency (e.g.,hyponatremia,hypoglycemia, others).[4][6][17][7][1][8] Lethargy is the most common side effect and has been found to occur in 31 to 70% of people treated with AG.[6] It is the most common reason for discontinuation of AG.[6] Skin rash and hypotension have both been observed in about 15% of people.[6] At least one side effect will occur in 45 to 85% of people.[6] Severe toxicity is seen in 10% of people, includingcirculatory collapse thought to be due to adrenal insufficiency.[6]Hematological andbone marrow toxicity, including marked depression ofwhite 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] Thecentral nervous system side effects of AG are due to its nature as an anticonvulsant and relation toglutethimide.[17]
In the event ofoverdose of AG,drowsiness,nausea,vomiting,hypotension, andrespiratory depression may occur.[19][20] Medical attention should be sought urgently.[19] Treatment of AG overdose can includegastric lavage to decreaseabsorption anddialysis to enhanceelimination.[21]
AG has aninteraction with all corticosteroids.[1] It enhances the metabolism ofdexamethasone, so hydrocortisone should be used instead.[8] If the person is takingwarfarin, the dosage of warfarin may need to be increased.[8]Alcohol potentiates thecentral nervous system side effects of AG.[8] Dosages oftheophylline,digitoxin, andmedroxyprogesterone acetate may need to be increased.[8]
AG is apotent andnon-selectivesteroidogenesis inhibitor, acting as areversible andcompetitive inhibitor of multiplesteroidogenic enzymes, including:[9][10][11][6][7]
As such, AG is anestrogen synthesis inhibitor andadrenal steroidogenesis inhibitor, including both anandrogen synthesis inhibitor and acorticosteroid synthesis inhibitor.[9][10][11][6][7] For these reasons, AG has functionalantiestrogenic,antiandrogenic,antiglucocorticoid, andantimineralocorticoid actions.[9][10][11][6][7] In terms of its actions as an adrenal steroidogenesis inhibitor, it is described as a form of reversible "medical adrenalectomy" or "chemical adrenalectomy".[4][6][8] While AG inhibits all of the enzymes listed above, inhibition of P450scc is primarily responsible for its inhibition ofadrenalsteroidogenesis.[25] In terms ofadrenal androgens, AG has been shown to significantly suppressdehydroepiandrosterone sulfate,androstenedione, testosterone, anddihydrotestosterone levels in men.[6] Although it is most potent in inhibiting aromatase among the enzymes it targets, AG is described nonetheless as a relatively weakaromatase 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 effectiveovarian steroidogenesis inhibitor in premenopausal women.[17] However, interference with ovarian steroidogenesis by AG may in any case result inhyperandrogenism andvirilization in premenopausal women.[8][7]
| Generation | Medication | Dosage | % inhibitiona | Classb | IC50c |
|---|---|---|---|---|---|
| First | Testolactone | 250 mg 4x/dayp.o. | ? | Type I | ? |
| 100 mg 3x/weeki.m. | ? | ||||
| Rogletimide | 200 mg 2x/dayp.o. 400 mg 2x/dayp.o. 800 mg 2x/dayp.o. | 50.6% 63.5% 73.8% | Type II | ? | |
| Aminoglutethimide | 250 mg mg 4x/dayp.o. | 90.6% | Type II | 4,500 nM | |
| Second | Formestane | 125 mg 1x/dayp.o. 125 mg 2x/dayp.o. 250 mg 1x/dayp.o. | 72.3% 70.0% 57.3% | Type I | 30 nM |
| 250 mg 1x/2 weeksi.m. 500 mg 1x/2 weeksi.m. 500 mg 1x/1 weeki.m. | 84.8% 91.9% 92.5% | ||||
| Fadrozole | 1 mg 1x/dayp.o. 2 mg 2x/dayp.o. | 82.4% 92.6% | Type II | ? | |
| Third | Exemestane | 25 mg 1x/dayp.o. | 97.9% | Type I | 15 nM |
| Anastrozole | 1 mg 1x/dayp.o. 10 mg 1x/dayp.o. | 96.7–97.3% 98.1% | Type II | 10 nM | |
| Letrozole | 0.5 mg 1x/dayp.o. 2.5 mg 1x/dayp.o. | 98.4% 98.9%–>99.1% | Type II | 2.5 nM | |
| Footnotes:a = Inpostmenopausal women.b = Type I:Steroidal,irreversible (substrate-binding site). Type II:Nonsteroidal,reversible (binding to and interference with thecytochrome P450hememoiety).c = Inbreast cancerhomogenates.Sources: See template. | |||||
Withoral administration, theabsorption of AG is rapid and complete.[1] It iswell-distributed throughout the body.[1] In terms ofmetabolism, a portion of AG isacetylated in theliver.[1] Thebiological half-life of AG is 12.5 hours.[1] It isexcreted inurine 34 to 54% unchanged.[1]
AG is anonsteroidalcompound, specifically aglutarimide, and is aderivative ofglutethimide.[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 torogletimide (pyridoglutethimide) andthalidomide, as well asamphenone B,metyrapone, andmitotane.[10][27][28][29][12]
AG was introduced for medical use, as ananticonvulsant, in 1960.[12][13] In 1963, it was reported that AG had induced symptoms ofAddison'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 ofbreast cancer was published in 1969, and the first report of AG in the treatment ofprostate 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 withtestolactone, it is described as a "first-generation" aromatase inhibitor.[7] AG has largely been superseded by medications with better effectiveness andtolerability and reduced toxicity, such asketoconazole,abiraterone acetate, and other aromatase inhibitors.[4][6][9]
Aminoglutethimide is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name, whileaminoglutéthimide is itsDCFTooltip Dénomination Commune Française andaminoglutetimide is itsDCITTooltip Denominazione Comune Italiana.[14][26][31][3] It is also known by its developmental code namesBa 16038,Ciba 16038, andND-1966.[14][26][31][3]
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]
AG appears to remain marketed only in a few countries, which includeChina,Egypt, andLithuania.[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 theUnited States,Canada, theUnited Kingdom, otherEuropean countries,Australia,New Zealand,South Africa,South America,Israel,Malaysia, andHong Kong.[31][7]
