Report on Aminoglutethimide (DB00357): A Comprehensive Monograph

Section 1: Executive Summary & Drug Identity

1.1 Overview of Aminoglutethimide: A Historical First-in-Class Agent

Aminoglutethimide is a nonsteroidal small molecule that holds a significant place in the history of endocrine therapy. It is recognized as a first-generation aromatase inhibitor and a potent inhibitor of steroidogenesis.[1] Its clinical journey is a notable case study in pharmaceutical development, marked by serendipitous discovery, drug repurposing, and eventual obsolescence in the face of more targeted and tolerable agents.

Initially introduced in 1960 under brand names such as Elipten, its intended use was as an anticonvulsant for the treatment of petit mal epilepsy.[1] However, its clinical use in this capacity was short-lived. By 1963, reports emerged of the drug inducing symptoms of adrenal insufficiency, a condition akin to Addison's disease.[1] These significant adverse endocrine effects led to its withdrawal from the market as an anticonvulsant in 1966.[1]

The very toxicity that led to its initial withdrawal—the suppression of adrenocortical steroid synthesis—was subsequently recognized as a powerful therapeutic mechanism. This pivotal realization led to the repurposing of aminoglutethimide for conditions characterized by hormonal excess. Beginning in 1969 for breast cancer and 1974 for prostate cancer, it was reintroduced under brand names like Cytadren and Orimeten for the management of Cushing's syndrome and hormone-dependent malignancies.[1] In this new role, it functioned as a "medical adrenalectomy" agent.[3]

Despite its utility, aminoglutethimide has been largely superseded by newer medications that offer superior efficacy, better tolerability, and a more favorable safety profile, including ketoconazole, abiraterone acetate, and third-generation aromatase inhibitors.[1] Nonetheless, its legacy is profound. Aminoglutethimide was the first aromatase inhibitor to be used clinically, and its success provided the crucial "proof-of-concept" that validated aromatase inhibition as a viable therapeutic strategy, directly paving the way for the development of modern endocrine therapies.[1] The drug has also seen off-label use in the bodybuilding community to modulate cortisol and estrogen levels, a practice that is considered high-risk and is prohibited in competitive sports.[1]

1.2 Key Identification and Physicochemical Properties

The fundamental identity of aminoglutethimide is defined by its specific chemical structure, physical properties, and various classification codes. It is a derivative of the glutarimide class of compounds, structurally related to the sedative glutethimide as well as to thalidomide.[1]

Its chemical identity is described by several systematic names, including 3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione and 2-(4-aminophenyl)-2-ethylglutarimide.[5] The molecular formula is

C13​H16​N2​O2​, with a corresponding molecular weight of approximately 232.28 g/mol.[5]

Physically, aminoglutethimide presents as a fine, white or creamy white crystalline powder.[5] Its solubility characteristics are critical to its formulation and absorption; it is very slightly soluble in water but is readily soluble in most organic solvents and forms water-soluble salts with strong acids, such as 0.1 M hydrochloric acid.[5] This allows for effective oral administration and absorption.

A consolidated summary of its key identifiers and properties is provided in Table 1.1.

Table 1.1: Summary of Aminoglutethimide Identifiers and Properties

Category	Identifier	Value	Source(s)
General Identifiers	Generic Name	Aminoglutethimide	3
	DrugBank ID	DB00357	15
	Type	Small Molecule	15
Chemical Identifiers	CAS Number	125-84-8	12
	Molecular Formula	C13​H16​N2​O2​	12
	Molecular Weight	232.28 g/mol	5
	IUPAC Name	3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione	5
	InChI Key	ROBVIMPUHSLWNV-UHFFFAOYSA-N	12
Commercial/Regulatory	Brand Names	Cytadren, Elipten, Orimeten, Aminoblastin	1
	ATC Code	L02BG01	15
	Developer	Ciba (Novartis)	9
Physical Properties	Appearance	Fine, white or creamy white crystalline powder	5
	Water Solubility	Very slightly soluble (~0.2 mg/mL)	9
	Organic Solvent Solubility	Readily soluble in methanol, DMSO, acetonitrile	9

Section 2: Comprehensive Pharmacological Profile

2.1 Mechanism of Action: Dual Inhibition of Steroidogenesis and Aromatization

Aminoglutethimide exerts its pharmacological effects through a potent but non-selective inhibition of several key cytochrome P-450 enzymes involved in steroid biosynthesis. This results in a dual mechanism of action: the broad suppression of adrenal steroidogenesis and the inhibition of peripheral aromatization.

Primary Mechanism - Steroidogenesis Inhibition:

The principal action of aminoglutethimide is the blockade of the first and rate-limiting step in the synthesis of all adrenal steroids.5 It competitively inhibits the cholesterol side-chain cleavage enzyme complex (P450scc, or CYP11A1), which is responsible for the enzymatic conversion of cholesterol to Δ5-pregnenolone.3 By blocking this initial step, aminoglutethimide effectively curtails the production of all downstream adrenal hormones, including glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgens.3 This comprehensive blockade is the basis for its description as a "medical adrenalectomy" agent.3

Secondary Mechanism - Aromatase Inhibition:

In addition to its effects on the adrenal gland, aminoglutethimide is a potent inhibitor of the aromatase enzyme (CYP19A1).6 This enzyme is responsible for the peripheral conversion of androgens, such as androstenedione and testosterone, into estrogens, namely estrone and estradiol.3 This action is particularly significant in postmenopausal women, in whom peripheral aromatization in adipose tissue, muscle, and the breast tumor itself is the primary source of circulating estrogens.12

Other Enzymatic Effects:

The drug's inhibitory action is not limited to P450scc and aromatase. It also blocks several other cytochrome P-450-mediated hydroxylation steps that occur later in the steroid synthesis pathway, including C-11, C-18, and C-21 hydroxylations.3 This broad, multi-target profile underscores its non-selective nature.

Stereospecific Activity:

The clinically available form of aminoglutethimide is a racemic mixture of its dextro (d) and levo (l) enantiomers.19 These enantiomers exhibit distinct pharmacological activities. The d-isomer is primarily responsible for the aromatase-inhibiting effect and is approximately 30 times more potent in this regard than the l-isomer.9 Conversely, the l-isomer is the more potent inhibitor of cholesterol side-chain cleavage and, therefore, of adrenal steroidogenesis.9 This stereospecificity demonstrates that the two principal mechanisms of the drug reside in different molecular configurations, a finding that would later inform the development of more selective inhibitors.

The broad, non-selective mechanism of aminoglutethimide is both its defining therapeutic feature and its greatest liability. Its ability to shut down the entire adrenal steroid production pathway makes it effective in conditions of severe hypercortisolism like Cushing's syndrome. However, this same lack of specificity is the direct cause of its extensive side effect profile. It does not discriminate between cortisol and essential mineralocorticoids, leading to risks of hypotension and adrenal insufficiency, and it also affects thyroid hormone synthesis.[3] This contrasts sharply with modern therapeutic agents, such as third-generation aromatase inhibitors (e.g., anastrozole, letrozole), which are highly selective for the aromatase enzyme and thus have far fewer off-target endocrine effects and superior tolerability.[21] Aminoglutethimide's pharmacology exemplifies an early, "blunt instrument" approach to endocrine therapy, the limitations of which necessitated complex clinical management and drove the search for more targeted successors.

2.2 Pharmacodynamics: Effects on Endocrine Pathways

The profound inhibition of steroid synthesis by aminoglutethimide triggers significant compensatory responses within the body's endocrine feedback loops, primarily affecting the adrenal and thyroid axes.

Adrenal Axis:

The primary pharmacodynamic consequence of aminoglutethimide administration is the disruption of the hypothalamic-pituitary-adrenal (HPA) axis. The drug-induced decrease in adrenal cortisol secretion is detected by the hypothalamus and pituitary gland. Via the negative feedback mechanism, the pituitary gland responds by dramatically increasing its secretion of adrenocorticotropic hormone (ACTH) in an attempt to stimulate the adrenal glands to produce more cortisol.3 This surge in ACTH can be substantial enough to overcome the competitive enzymatic blockade by aminoglutethimide, leading to a resumption of steroid synthesis. This phenomenon, known as "adrenal escape" or the "escape phenomenon," can limit the long-term efficacy of the drug, particularly in patients with pituitary-dependent Cushing's syndrome.11 This physiological response is not a failure of the drug itself but a testament to the robustness of the endocrine feedback system. It is the fundamental reason why concomitant administration of a replacement glucocorticoid, such as hydrocortisone, is mechanistically essential. Hydrocortisone serves two critical purposes: it replaces the deficient cortisol, preventing symptoms of adrenal insufficiency, and it provides the necessary negative feedback to the pituitary to suppress ACTH secretion, thereby preventing the escape phenomenon and allowing aminoglutethimide to maintain its inhibitory effect.3

Thyroid Axis:

Aminoglutethimide also interferes with thyroid function by inhibiting the synthesis of thyroxine.3 This can lead to clinical or subclinical hypothyroidism. Similar to the HPA axis, the pituitary responds to falling thyroid hormone levels with a compensatory increase in thyroid-stimulating hormone (TSH). In many cases, this TSH rise is sufficient to overcome the blockade and maintain euthyroid status.3 However, hypothyroidism remains a significant risk, necessitating regular monitoring of thyroid function and, in some patients, replacement therapy with thyroxine.1

Gonadal Function:

A key pharmacodynamic feature of aminoglutethimide is its site of action. While it is a potent inhibitor of adrenal steroidogenesis and peripheral aromatization, it does not suppress estrogen production by the ovaries in premenopausal women.17 Ovarian estrogen synthesis is driven primarily by gonadotropins (LH and FSH) rather than ACTH and is less susceptible to the drug's effects. This is a critical distinction that explains why its use in breast cancer treatment is largely restricted to postmenopausal women, in whom the ovaries are no longer the primary source of estrogen.12

2.3 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic profile of aminoglutethimide is characterized by rapid and complete absorption, predictable distribution, and clearance primarily through renal excretion of both the parent drug and its major metabolite.

Absorption:

Following oral administration, aminoglutethimide is rapidly and almost completely absorbed from the gastrointestinal tract. Its systemic bioavailability is high, estimated to be between 92% and 98%.19 Studies have shown that the bioavailability from tablets is equivalent to that of an equal dose administered as an oral solution, indicating efficient formulation.5

Distribution:

Maximum plasma concentrations (Cmax​) are achieved relatively quickly. In healthy male volunteers administered a 500 mg dose (two 250-mg tablets), the average Cmax​ was 5.9 µg/mL, reached at a median time (Tmax​) of 1.5 hours.5

Metabolism:

A substantial portion of an aminoglutethimide dose is metabolized, with the primary pathway being N-acetylation to form the N-acetyl derivative.5 Aminoglutethimide is also a known inducer of hepatic enzymes, a property that underlies many of its significant drug-drug interactions by accelerating the metabolism of co-administered substrates.6

Excretion:

The drug and its metabolite are eliminated from the body primarily via the kidneys. Following a single oral dose, between 34% and 54% is excreted in the urine as unchanged parent drug within the first 48 hours. An additional fraction is eliminated as the N-acetyl derivative.3 The elimination half-life (

t1/2​) of aminoglutethimide is approximately 12.5 hours.[3]

The key pharmacokinetic parameters are summarized in Table 2.1.

Table 2.1: Key Pharmacokinetic Parameters of Aminoglutethimide

Parameter	Value	Clinical Implication	Source(s)
Bioavailability	92-98%	High and reliable absorption after oral dosing.	19
Tmax​ (Time to Peak Plasma Concentration)	~1.5 hours	Rapid onset of systemic exposure.	5
Elimination Half-life (t1/2​)	~12.5 hours	Supports multiple daily dosing (e.g., every 6 hours) to maintain steady-state concentrations.	3
Primary Metabolism Route	N-acetylation	Produces a major metabolite for excretion.	5
Primary Excretion Route	Renal	Dose adjustments may be needed in severe renal impairment.	5
Percent Excreted Unchanged (Urine)	34-54%	A significant portion of the drug is cleared without being metabolized.	5

Section 3: Clinical Applications, Efficacy, and Dosing

3.1 Management of Cushing's Syndrome

Aminoglutethimide is indicated for the suppression of adrenal function in selected patients with Cushing's syndrome.[3] Its powerful steroidogenesis-inhibiting properties make it effective in controlling the severe hypercortisolism that characterizes this condition, regardless of whether the underlying cause is an adrenal tumor, adrenal hyperplasia, or an ectopic ACTH-producing tumor.[1]

The primary role of aminoglutethimide in this setting is as a temporizing or palliative measure. Because it blocks hormone production but does not affect the underlying disease process (e.g., the tumor itself), it is used primarily as an interim therapy to stabilize patients before more definitive treatment, such as surgery, can be undertaken.[5] It is also used in patients for whom surgery is not appropriate or has failed.

In terms of efficacy, aminoglutethimide has been shown to be effective in lowering cortisol levels. During 1-3 months of therapy, morning plasma cortisol levels were reduced, on average, to approximately one-half of pretreatment levels in patients with adrenal carcinoma or ectopic ACTH-producing tumors, and to about two-thirds of pretreatment levels in those with adrenal hyperplasia.[5] Overall, clinical improvement is observed in approximately 56% of patients with Cushing's syndrome treated with the drug.[18] However, its long-term efficacy can be compromised by the "escape phenomenon," where rising ACTH levels overcome the adrenal blockade, particularly in patients with pituitary-dependent disease.[11]

3.2 Treatment of Hormone-Dependent Malignancies

3.2.1 Metastatic Breast Cancer

Aminoglutethimide was a key agent in the treatment of advanced, hormone receptor-positive breast cancer, particularly in postmenopausal women.[1] Its mechanism in this context relies on its ability to inhibit the aromatase enzyme, thereby blocking the peripheral conversion of androgens to estrogens.[6] In postmenopausal women, this peripheral synthesis is the main source of estrogen that can fuel the growth of estrogen receptor-positive tumors.

Clinical studies demonstrated significant efficacy, with aminoglutethimide producing objective disease regression in 32% of unselected postmenopausal patients and in a more impressive 52% of women whose tumors were confirmed to be estrogen receptor-positive.[18] Its effectiveness was considered comparable to that of surgical adrenalectomy, which was a standard of care at the time.[18] It was often positioned as a second-line hormonal therapy for patients who had relapsed or failed to respond to tamoxifen. Response rates in patients who had previously responded to tamoxifen were as high as two-thirds, and up to 30% of initial tamoxifen non-responders also responded to subsequent treatment with aminoglutethimide.[19] The drug was also indicated for use in male patients with metastatic breast carcinoma.[19]

3.2.2 Advanced Prostate Cancer

Aminoglutethimide has also been used in the management of advanced prostate cancer.[1] Its mechanism of action in this disease is the inhibition of adrenal steroidogenesis, which blocks the production of adrenal androgens that can continue to stimulate prostate cancer growth even after testicular androgen production has been suppressed (i.e., after surgical or medical castration).[3]

However, its effectiveness in prostate cancer has been described as low and inconsistent.[1] This is likely attributable to its relatively weak inhibition of steroidogenesis compared to newer agents and its suboptimal pharmacokinetic profile.[1] Despite these limitations, it was considered a viable option for achieving a "medical adrenalectomy" in castration-resistant settings. Clinical trials continued to investigate its use in this context, for example, a Phase II trial initiated in 2000 studied hydrocortisone combined with either aminoglutethimide or ketoconazole in patients with prostate cancer after antiandrogen withdrawal.[23]

3.3 Historical Indication: Epilepsy

The first clinical application of aminoglutethimide was not in endocrinology or oncology, but in neurology. It was introduced to the market in 1960 under the brand name Elipten as an anticonvulsant for the treatment of petit mal epilepsy.[1] However, the emergence of its profound and often severe endocrine side effects, particularly adrenal suppression, rendered its risk-benefit profile unfavorable for this indication. Consequently, it was withdrawn from the market for the treatment of epilepsy in 1966.[1]

3.4 Off-Label and Non-Medical Uses

Beyond its approved medical indications, aminoglutethimide has been used illicitly by bodybuilders and other athletes for two main purposes.[1] Firstly, it is used to lower circulating levels of cortisol, a catabolic hormone that promotes muscle protein breakdown. By suppressing cortisol, users aim to prevent muscle loss, particularly during intense training or cutting cycles. Secondly, it is used for its aromatase-inhibiting properties to counteract the estrogenic side effects of anabolic-androgenic steroid use, such as gynecomastia (development of breast tissue), increased water retention, and fat gain.[1]

The actual utility of aminoglutethimide for these purposes has been questioned, with anecdotal reports suggesting few positive outcomes, while the health risks associated with its unsupervised use are considered to be high.[1] Due to its performance-enhancing potential and health risks, the use of aminoglutethimide and other aromatase inhibitors is prohibited in male athletes by the World Anti-Doping Agency (WADA), and sensitive methods for its detection in urine have been developed for anti-doping screening.[8]

3.5 Dosing, Administration, and Therapeutic Monitoring

The administration of aminoglutethimide requires careful management and close monitoring due to its narrow therapeutic index and significant potential for toxicity.

Administration and Dosing:

Aminoglutethimide is administered orally in the form of 250 mg tablets.5 For the treatment of Cushing's syndrome, it is strongly recommended that therapy be initiated in a hospital setting to ensure patient safety and allow for stabilization of the dosage regimen.5 The typical starting dosage is 250 mg administered four times daily, preferably at 6-hour intervals, for a total daily dose of 1 g.5 The patient's response must be closely followed by monitoring plasma cortisol levels. If cortisol suppression is inadequate, the dosage can be increased in increments of 250 mg daily at intervals of 1-2 weeks, up to a maximum total daily dose of 2 g.5 Dose reduction or temporary discontinuation may be necessary in the event of adverse effects like extreme drowsiness, severe skin rash, or excessive cortisol suppression.5

Required Concomitant Therapy:

Due to the drug's mechanism of action and the body's physiological response, concomitant hormone replacement is mandatory.

• Glucocorticoid Replacement: To prevent adrenal insufficiency and to suppress the compensatory rise in ACTH, daily replacement with a glucocorticoid is essential. Hydrocortisone, typically at a dose of 20-30 mg orally per day, is the agent of choice.[3] Dexamethasone should not be used, as aminoglutethimide accelerates its metabolism.[3]
• Mineralocorticoid Replacement: Since aminoglutethimide also suppresses aldosterone production, some patients may require mineralocorticoid replacement with fludrocortisone to prevent hypotension and electrolyte imbalances.[5]

Therapeutic Monitoring:

Patients receiving aminoglutethimide require intensive monitoring, including:

• Plasma Cortisol Levels: To guide dose titration and ensure adequate suppression without inducing severe adrenal insufficiency.[5]
• Blood Pressure: Regular monitoring for hypotension, particularly orthostatic hypotension.[6]
• Complete Blood Counts: To detect signs of rare but serious hematologic toxicity, such as leukopenia or thrombocytopenia.[6]
• Thyroid Function Tests: To monitor for drug-induced hypothyroidism.[6]
• Liver Function Tests: To assess for potential hepatotoxicity.[6]

Section 4: Detailed Safety and Tolerability Analysis

The clinical utility of aminoglutethimide is significantly limited by its extensive and frequent adverse effects. The drug is associated with a high incidence of toxicity, which, while often reversible, frequently necessitates dose reduction or discontinuation of therapy.

4.1 Adverse Drug Reactions by System Organ Class

The safety profile of aminoglutethimide is broad, affecting multiple organ systems. Side effects are reported to occur in approximately two-thirds of all patients.[24] Between 5% and 10% of individuals discontinue the medication due to intolerable adverse reactions.[1]

The prominent drowsiness associated with aminoglutethimide is not a random neurological effect but is a direct consequence of its chemical origins. Aminoglutethimide is a structural derivative of glutethimide, a compound that was marketed as a hypnotic-sedative drug.[1] This clear structure-activity relationship explains why CNS depression is the most common and dose-limiting side effect of aminoglutethimide, providing a mechanistic understanding of its primary toxicity.

A summary of adverse reactions, organized by system organ class and frequency, is presented in Table 4.1.

Table 4.1: Frequency and Severity of Adverse Reactions to Aminoglutethimide

System Organ Class	Frequency	Adverse Reaction	Clinical Notes and Management	Source(s)
Nervous System	Very Common (>10%)	Drowsiness, Lethargy, Somnolence	Occurs in up to 1 in 3 patients. Dose-related, often transient, but is the main reason for discontinuation. Patients should be warned against driving or operating machinery.	1
	Common (1-10%)	Dizziness, Ataxia, Weakness, Headache	Dizziness may be related to orthostatic hypotension. Ataxia can impair coordination.	1
Dermatologic	Very Common (>10%)	Morbilliform Skin Rash	Occurs in approx. 1 in 6 patients. Often appears early and may resolve with continued therapy. Discontinue if rash persists >8 days or becomes severe.	5
	Common (1-10%)	Pruritus (Itching)	Reported in approx. 1 in 20 patients.	5
	Rare (<0.1%)	Stevens-Johnson Syndrome, Urticaria	Severe, life-threatening hypersensitivity reactions.	20
Gastrointestinal	Very Common (>10%)	Nausea, Anorexia (Loss of Appetite)	Occurs in approx. 1 in 8 patients. Usually lessens with continued therapy.	5
	Common (1-10%)	Vomiting	Occurs in approx. 1 in 30 patients.	5
Endocrine	Common (1-10%)	Adrenal Insufficiency	An on-target effect, especially under stress. Manifests as hypotension, weakness, hyponatremia. Requires glucocorticoid and possibly mineralocorticoid replacement.	6
	Uncommon (<1%)	Hypothyroidism	May be associated with thyroid enlargement. Requires monitoring of thyroid function.	6
	Rare (<0.1%)	Virilization (in females), Precocious Puberty (in males)	Hirsutism and masculinization have been reported.	20
Cardiovascular	Common (1-10%)	Hypotension (including orthostatic)	Occurs in approx. 1 in 30 patients. Due to suppressed aldosterone. Requires blood pressure monitoring.	5
	Common (1-10%)	Tachycardia	Occurs in approx. 1 in 40 patients.	5
Hematologic	Rare (<0.1%)	Leukopenia, Thrombocytopenia, Agranulocytosis, Pancytopenia	Occurs in ~0.9% of patients. Potentially fatal. Requires immediate discontinuation and supportive care.	6
Hepatic	Uncommon (<1%)	Elevated Liver Enzymes	Isolated instances of abnormal liver function tests reported.	5
	Rare (<0.1%)	Hepatotoxicity, Cholestatic Jaundice	Suspected hepatotoxicity is very rare (<1 in 1000 patients).	5
Metabolic	Common (1-10%)	Hypercholesterolemia	Elevations in total cholesterol and LDL are common, likely due to blockade of cholesterol metabolism.	1

4.2 Contraindications and High-Risk Populations

The use of aminoglutethimide is contraindicated in several patient populations due to its potential for severe harm.

• Absolute Contraindications: The drug should not be used in individuals with a known hypersensitivity to aminoglutethimide or its parent compound, glutethimide.[1]
• Pregnancy and Lactation: Aminoglutethimide is strictly contraindicated during pregnancy. Animal studies have demonstrated teratogenicity, including fetal deaths, decreased fetal implantation, and pseudohermaphroditism in female offspring.[5] Patients of childbearing potential must be apprised of the potential hazard to a fetus.[5] It is not known if the drug is excreted in human milk, but given the potential for serious adverse reactions in a nursing infant, a decision must be made to either discontinue the drug or discontinue breastfeeding.[1]
• High-Risk Medical Conditions: Caution is required in patients with pre-existing conditions. These include kidney or liver disease, as impaired clearance may increase drug exposure and toxicity.[1] It should also be used with caution in patients with hypothyroidism, as the drug can exacerbate this condition.[1] Patients with active infections, including chickenpox or shingles (herpes zoster), are at risk of severe disseminated disease due to the drug's effects on the adrenal stress response.[1]

4.3 Management of Overdose and Toxicity

Overdose of aminoglutethimide is a medical emergency that can lead to profound central nervous system and cardiovascular depression.

• Symptoms: The clinical manifestations of overdose include extreme drowsiness, lethargy, somnolence, ataxia, dizziness, fatigue, nausea, and vomiting.[1] In severe cases, this can progress to coma, respiratory depression, hypotension, and hypovolemic shock due to dehydration.[1]
• Treatment: Management is primarily supportive and aimed at reducing drug absorption and enhancing its elimination. Urgent medical attention is required. Treatment measures can include gastric lavage to empty the stomach contents and decrease further absorption, along with dialysis to enhance the elimination of the drug from the bloodstream.[1]

4.4 Clinically Significant Drug Interactions

Aminoglutethimide is a potent inducer of hepatic enzymes, which significantly affects the metabolism of numerous other drugs, often reducing their efficacy.[6] Its own pharmacodynamic effects also lead to important interactions. A summary of key interactions is provided in Table 4.2.

Table 4.2: Aminoglutethimide Drug Interaction Profile

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Recommended Management	Source(s)
Dexamethasone	Hepatic Enzyme Induction	Accelerated metabolism and decreased therapeutic efficacy of dexamethasone.	Avoid co-administration. Use hydrocortisone for glucocorticoid replacement, as its metabolism is not significantly affected.	1
Warfarin and other Coumarin Anticoagulants	Hepatic Enzyme Induction	Accelerated metabolism leading to a diminished anticoagulant effect and increased risk of thrombosis.	The dosage of warfarin may need to be significantly increased. Monitor INR closely and adjust the anticoagulant dose accordingly.	1
Alcohol and other CNS Depressants	Pharmacodynamic Synergism	Potentiation of central nervous system side effects, such as drowsiness, dizziness, and impaired coordination.	Advise patients to use alcohol cautiously or avoid it completely. Use with other CNS depressants requires caution.	1
Theophylline, Digitoxin, Medroxyprogesterone Acetate	Hepatic Enzyme Induction	Increased metabolism and decreased plasma concentrations, leading to reduced therapeutic effect.	Dosages of these medications may need to be increased. Therapeutic drug monitoring is advised where applicable.	1
Live Virus Vaccines	Immunosuppression	Aminoglutethimide can weaken the body's immune response, potentially increasing the risk of infection from live vaccines and reducing vaccine efficacy.	Use with live vaccines (e.g., measles, mumps, rubella, varicella) is generally not recommended or requires significant caution.	27
Other Corticosteroids (e.g., Amcinonide, Beclomethasone)	Hepatic Enzyme Induction	Increased metabolism and decreased therapeutic efficacy of the corticosteroid.	The efficacy of co-administered corticosteroids may be reduced.	3

Section 5: Regulatory History and Market Status

The regulatory and market lifecycle of aminoglutethimide is a compelling narrative that mirrors the evolution of pharmaceutical science and drug regulation over half a century. Its journey from a failed anticonvulsant to a repurposed endocrine therapy, and finally to a superseded historical agent, provides a clear illustration of scientific progress.

5.1 Developmental Timeline: From Anticonvulsant to "Medical Adrenalectomy"

• 1960: Aminoglutethimide was first introduced for medical use by Ciba (a predecessor of Novartis) under the brand name Elipten. Its approved indication was as an anticonvulsant for epilepsy.[1] This launch occurred in an era of drug development where primary effects were identified without a full understanding of a compound's broader pharmacological profile.
• 1963: The first clinical report linking aminoglutethimide to symptoms of adrenal insufficiency was published, signaling the discovery of its potent, and at the time, unwanted endocrine effects.[1]
• 1966: Due to accumulating evidence of its toxicity, particularly its effects on the adrenal gland, the drug was withdrawn from the market as an anticonvulsant.[1] This withdrawal highlights the early stages of post-marketing surveillance.
• 1969-1974: In a classic example of drug repurposing, researchers recognized that the "toxic" side effect was a powerful therapeutic mechanism. The first report of its use in breast cancer appeared in 1969, followed by its first reported use in prostate cancer in 1974.[1] This marked a shift towards a more mechanistic understanding of disease, recognizing the role of hormones in cancer growth.
• October 28, 1980: Reflecting its new therapeutic role, aminoglutethimide was approved by the U.S. Food and Drug Administration (FDA) under the brand name Cytadren for the treatment of Cushing's syndrome.[30] This re-approval demonstrated the adaptability of regulatory bodies to new scientific evidence.
• Legacy: Aminoglutethimide is historically recognized as one of the first adrenal steroidogenesis inhibitors and, crucially, the first aromatase inhibitor to be used clinically. Its success established the therapeutic validity of targeting hormone synthesis pathways, a concept that became a cornerstone of modern oncology.[1]

5.2 Global Market Withdrawal and Current Availability

The clinical prominence of aminoglutethimide waned with the advent of more advanced therapies. Its non-selective mechanism, high toxicity profile, and the complex management it required all spurred the development of superior agents. It has been largely superseded by newer drugs like ketoconazole and abiraterone acetate for steroidogenesis inhibition, and particularly by the highly selective and well-tolerated third-generation aromatase inhibitors (anastrozole, letrozole, exemestane) for breast cancer.[1]

• U.S. Market Status: The drug is no longer marketed in the United States. Novartis Pharmaceuticals Corp., the holder of the New Drug Application (NDA 18-202) for Cytadren, requested a voluntary withdrawal of approval from the FDA. This was part of a larger action involving multiple drugs. The withdrawal became effective on June 18, 2009.[31] Major drug information resources now list the availability of Cytadren in the U.S. as "Discontinued".[33] This final withdrawal was not prompted by a new safety concern but was a market-driven decision reflecting the drug's obsolescence in the face of better alternatives.
• European Market Status: The drug's status in Europe is less definitive. A 2019 European Medicines Agency (EMA) document mentioned aminoglutethimide as being among the medicines authorized in some EU member states for the treatment of Cushing's syndrome.[34] However, it is not widely available, and its use is likely very limited.
• Current Global Status: Today, aminoglutethimide remains commercially marketed in only a few countries worldwide.[1] It is, however, readily available from numerous chemical and pharmaceutical supply companies, but these products are intended strictly for research and manufacturing purposes and are not for diagnostic or therapeutic use in humans.[13]

Section 6: Concluding Analysis and Legacy

6.1 Synthesis of the Risk-Benefit Profile

The clinical value of any therapeutic agent is determined by a careful weighing of its benefits against its risks. For aminoglutethimide, this balance has shifted dramatically over time with the evolution of medical science.

In its time, the benefits of aminoglutethimide were substantial. It was an effective agent for rapidly lowering dangerously high cortisol levels in patients with severe Cushing's syndrome, providing a critical bridge to definitive therapy or a palliative option where none existed. In oncology, it offered a moderately effective hormonal therapy for advanced breast and prostate cancer in an era when treatment options were limited, providing responses comparable to major surgical interventions like adrenalectomy.

However, these benefits came at the cost of significant risks. The drug's safety profile is poor by modern standards, characterized by a very high incidence of adverse effects, particularly debilitating CNS depression and skin rashes that led to discontinuation in a notable percentage of patients. Its non-selective mechanism necessitated complex and burdensome clinical management, including mandatory hormone replacement and intensive monitoring of multiple organ systems to mitigate the risks of adrenal insufficiency, hypotension, and hypothyroidism. Furthermore, it carried the risk of rare but potentially fatal hematologic and hypersensitivity reactions.

When compared to the highly targeted, well-tolerated, and often more effective agents available today, the risk-benefit profile of aminoglutethimide is decidedly unfavorable for nearly all its former indications. Its clinical use in the modern era would be difficult to justify outside of exceptional circumstances, such as the unavailability of all other alternatives.

6.2 Aminoglutethimide's Legacy and the Evolution of Endocrine Therapies

While aminoglutethimide itself has been relegated to the annals of pharmaceutical history, its impact on the fields of endocrinology and oncology is profound and enduring. Its primary legacy is not as a modern therapeutic, but as a pioneering "proof-of-concept" drug that fundamentally validated a novel therapeutic strategy.

Aminoglutethimide was the first clinically successful aromatase inhibitor and steroidogenesis inhibitor.[1] Its ability to induce tumor regression in breast cancer patients by blocking estrogen synthesis provided the definitive clinical evidence that this pathway was a viable therapeutic target. This success directly catalyzed the research and development efforts that led to the creation of the modern aromatase inhibitors.

The very limitations of aminoglutethimide—its lack of specificity, its high toxicity, and the complexity of its use—served as the blueprint for what to improve upon. The pharmaceutical industry was driven to develop agents that could replicate its beneficial aromatase-inhibiting effect without its detrimental off-target actions. This pursuit of specificity and safety culminated in the second- and third-generation aromatase inhibitors, which are now a cornerstone of adjuvant and metastatic breast cancer treatment worldwide.

In conclusion, aminoglutethimide represents a critical evolutionary step in the transition from broad-spectrum cytotoxic chemotherapy to targeted, mechanism-based therapies. It was an indispensable tool that, despite its flaws, opened the door to a new class of treatment. While it is no longer a drug of choice, the principles it helped establish continue to benefit countless patients today.

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