フルオキシメステロン

DEA Schedule III Controlled Substance -> Anabolic steroids

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Genito-urinary system and sex hormones -> Sex hormones and modulators of the genital system

log Kow = 2.38

2

2.38

Crystals

WHITE SOLID

White or practically white crystalline powder

Soluble in pyridine; slightly soluble in acetone, chloroform; sparingly soluble in methanol; practically insoluble in water, ether, benzene, hexanes

4.52e-02 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

About 240 °C with some decomposition

270 °C

Warning

H361 (97.6%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 42 reports by companies from 4 notifications to the ECHA C&L Inventory.

Hazard Traits - Developmental Toxicity

DEA schedule III controlled substance

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation containing any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts of isomers is possible within the specific chemical designation. DEA Code #: 4000; Drug class: anabolic steroids.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluoxymesterone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.

Fluoxymesterone may potentiate the action of oral anticoagulants, causing bleeding in some patients. When fluoxymesterone therapy is initiated in patients receiving oral anticoagulants, dosage reduction of the anticoagulant may be required to prevent an excessive hypoprothrombinemic response. Patients receiving oral anticoagulants also should be closely monitored when androgen therapy is discontinued.

/Concurrent use of androgens with other hepatotoxic medications/ may result in an increased incidence of hepatotoxicity; patients should be carefully monitored, especially those undergoing long-term therapy or those with a history of liver disease. /Androgens/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 470(SRC), determined from a log Kow of 2.38(2) and a regression-derived equation(3), indicates that fluoxymesterone is expected to have moderate mobility in soil(SRC). Volatilization of fluoxymesterone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.1X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Fluoxymesterone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.5X10-10 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 470(SRC), determined from a log Kow of 2.38(2) and a regression-derived equation(3), indicates that fluoxymesterone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.1X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 14(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fluoxymesterone, which has an estimated vapor pressure of 6.5X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the atmosphere. Particulate-phase fluoxymesterone may be removed from the air by wet and dry deposition(SRC). Fluoxymesterone does not absorb light at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION: Fluoxymesterone is an anabolic steroid for systemic use. Origin of the substance: Naturally occuring anabolic steroids are synthesised in the testis, ovary and adrenal gland from cholesterol via pregnenolone. Synthetic anabolic steroids are based on the principal male hormone testosterone, modified in one of three ways: alkylation of the 17-carbon; esterification of the 17-OH group; modification of the steroid nucleus. The drug is a white solid crystal. It is practically insoluble in water; sparingly soluble in alcohol; slightly soluble in chloroform. The only legitimate therapeutic indications for anabolic steroids are: Replacement of male sex steroids in men who have androgen deficiency, for example as a result of loss of both testes. The treatment of certain rare forms of aplastic anaemia which are or may be responsive to anabolic androgens. The drugs have been used in certain countries to counteract catabolic states, for example after major trauma. HUMAN EXPOSURE: Main risks and target organs: There is no serious risk from acute poisoning, but chronic use can cause harm. The main risks are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. Summary of clinical effects: Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exaggeration of male characteristics and effects related to male hormones. Anabolic steroids can influence sexual function. They can also cause cardiovascular and hepatic damage. Acne and male-pattern baldness occur in both sexes; irregular menses, atrophy of the breasts, and clitoromegaly in women; and testicular atrophy and prostatic hypertrophy in men. Contraindications: Known or suspected cancer of the prostate or (in men) breast. Pregnancy or breast-feeding. Known cardiovascular disease is a relative contraindication. Routes of exposure: Oral: Anabolic steroids can be absorbed from the gastrointestinal tract, but many compounds undergo such extensive first-pass metabolism in the liver that they are inactive. Those compounds in which substitution of the 17-carbon protects the compound from the rapid hepatic metabolism are active orally. There are preparations of testosterone that can be taken sublingually. Parenteral: Intramuscular or deep subcutaneous injection is the principal route of administration of all the anabolic steroids except the 17-alpha-substituted steroids which are active orally. Absorption by route of exposure: The absorption after oral dosing is rapid for testosterone and probably for other anabolic steroids, but there is extensive first-pass hepatic metabolism for all anabolic steroids except those that are substituted at the 17-alpha position. The rate of absorption from subcutaneous or intramuscular depots depends on the product and its formulation. Absorption is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions. Distribution by route of exposure: The anabolic steroids are highly protein bound, and is carried in plasma by a specific protein called sex-hormone binding globulin. Biological half-life by route of exposure: The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots, and on the de-esterification which precedes it. Metabolism: Free (de-esterified) anabolic androgens are metabolized by hepatic mixed function oxidases. Elimination by route of exposure: After administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine, and 6% in the feces; there is some enterohepatic recirculation. Mode of action: Toxicodynamics: The toxic effects are an exaggeration of the normal pharmacological effects. Pharmacodynamics: Anabolic steroids bind to specific receptors present especially in reproductive tissue, muscle and fat. The anabolic steroids reduce nitrogen excretion from tissue breakdown in androgen deficient men. They are also responsible for normal male sexual differentiation. Carcinogenicity: Anabolic steroids may be carcinogenic. They can stimulate growth of sex hormone dependent tissue, primarily the prostate gland in men. Precocious prostatic cancer has been described after long-term anabolic steroid abuse. Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported. Teratogenicity: Androgen ingestion by a pregnant mother can cause virilization of a female fetus. Main adverse effects: The adverse effects of anabolic steroids include weight gain, fluid retention, and abnormal liver function as measured by biochemical tests. Administration to children can cause premature closure of the epiphyses. Men can develop impotence and azoospermia. Women are at risk of virilization. Chronic poisoning: Ingestion: Hepatic damage, manifest as derangement of biochemical tests of liver function and sometimes severe enough to cause jaundice; virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes; psychiatric disturbances can occur during or after prolonged treatment. Parenteral exposure: Virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes. Psychiatric disturbances can occur during or after prolonged treatment. Hepatic damage is not expected from parenteral preparations. Course, prognosis, cause of death: Patients with symptoms of acute poisoning are expected to recover rapidly. Patients who persistently abuse high doses of anabolic steroids are at risk of death from premature heart disease or cancer, especially prostatic cancer. Non-fatal but long-lasting effects include voice changes in women and fusion of the epiphyses in children. Other effects are reversible over weeks or months. Systematic description of clinical effects: Cardiovascular: Chronic ingestion of high doses of anabolic steroids can cause elevations in blood pressure, left ventricular hypertrophy and premature coronary artery disease. Neurological: Central nervous system: Stroke has been described in a young anabolic steroid abuser. Mania and psychotic symptoms of hallucination and delusion in anabolic steroid abusers has been described. They also described depression after withdrawal from anabolic steroids. There is also considerable debate about the effects of anabolic steroids on aggressive behavior. Mood swings were significantly more common in normal volunteers during the active phase of a trial comparing methyltestosterone with placebo. Gastrointestinal: Acute ingestion of large doses can cause nausea and gastrointestinal upset. Hepatic: Orally active (17-alpha substituted) anabolic steroids can cause abnormalities of hepatic function, manifest as abnormally elevated hepatic enzyme activity in biochemical tests of liver function, and sometimes as overt jaundice. The histological abnormality of peliosis hepatis has been associated with anabolic steroid use. Angiosarcoma and a case of hepatocellular carcinoma in an anabolic steroid user has been reported. Urinary: Men who take large doses of anabolic steroids can develop prostatic hypertrophy. Prostatic carcinoma has been described in young men who have abused anabolic steroids. Endocrine and reproductive systems: Small doses of anabolic steroids are said to increase libido, but larger doses lead to azoospermia and impotence. Testicular atrophy is a common clinical feature of long-term abuse of anabolic steroids, and gynecomastia can occur. Women develop signs of virilism, with increased facial hair, male pattern baldness, acne, deepening of the voice, irregular menses and clitoral enlargement. Dermatological: Acne occurs in both male and female anabolic steroids abusers. Women can develop signs of virilism, with increased facial hair and male pattern baldness. Eye, ear, nose, throat: local effects: Changes in the larynx in women caused by anabolic steroids can result in a hoarse, deep voice. The changes are irreversible. Hematological: Anabolic androgens stimulate erythropoiesis. Metabolic: Fluid and electrolyte disturbances: Sodium and water retention can occur, and result in oedema; hypercalcemia is also reported. Others: Insulin resistance with a fall in glucose tolerance, and hypercholesterolemia with a fall in high density lipoprotein cholesterol, have been reported.

Fluoxymesterone is a synthetic androgenic anabolic steroid and is approximately 5 times as potent as natural methyltestosterone. Like testosterone and other androgenic hormones, fluoxymesterone binds to the androgen receptor. It produces retention of nitrogen, sodium, potassium, and phosphorus; increases protein anabolism; decreases amino acid catabolism and decreased urinary excretion of calcium. The antitumour activity of fluoxymesterone appears related to reduction or competitive inhibition of prolactin receptors or estrogen receptors or production.

The Koc of fluoxymesterone is estimated as 470(SRC), using a log Kow of 2.38(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that fluoxymesterone is expected to have moderate mobility in soil.

/SIGNS AND SYMPTOMS/ Hepatic neoplasms have been associated with long-term, high-dose androgen therapy in humans; some cases were irreversible after androgen withdrawal. This effect is more likely with oral methylated androgens. /Androgens/

/SIGNS AND SYMPTOMS/ In males, oligospermia, azoospermia, or reduced sperm function or ejaculatory volume resulting in possible infertility may occur during high-dose therapy with androgens if spermatogenesis is suppressed by a negative feedback mechanism. In females treated with androgens, amenorrhea may result, impairing fertility. In both females and males, fertility usually returns following cessation of therapy in females and dosage reduction or discontinuation in males. /Androgens/

/SIGNS AND SYMPTOMS/ Fluoxymesterone may cause fetal harm when administered to pregnant women. Androgenic effects including clitoral hypertrophy, labial fusion of the external genitalia to form a scrotal-like structure, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy.

/CASE REPORTS/ Peliosis hepatis was encountered in 12 patient treated with high-dose fluoxymesterone therapy. In 3 cases liver failure was primary cause of death.

/CASE REPORTS/ Prostate cancer developed in 2 male pt being treated with fluoxymesterone for erectile impotence.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Fluoxymesterone

Ambiguous-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 14 was calculated for fluoxymesterone(SRC), using a log Kow of 2.38(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for fluoxymesterone is estimated as 6.1X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that fluoxymesterone is expected to be essentially nonvolatile from moist soil(SRC) and water surfaces(2). Fluoxymesterone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.5X10-10 mm Hg(SRC), determined from a fragment constant method(3).

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation containing any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts of isomers is possible within the specific chemical designation. DEA Code #: 4000; Drug class: anabolic steroids.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fluoxymesterone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

G - Genito urinary system and sex hormones

QG - Genito urinary system and sex hormones

Fluoxymesterone is a synthetic androgen, or male hormone, similar to testosterone. Fluoxymesterone works by attaching itself to androgen receptors; this causes it to interact with the parts of the cell involved in the making of proteins. It may cause an increase in the synthesis of some proteins or a decrease in the synthesis of others. These proteins have a variety of effects, including blocking the growth of some types of breast cancer cells, stimulating cells that cause male sexual characteristics, and stimulating the production of red blood cells.

Fluoxymesterone is a synthetic androgenic anabolic steroid and is approximately 5 times as potent as natural methyltestosterone. Like testosterone and other androgenic hormones, fluoxymesterone binds to the androgen receptor. It produces retention of nitrogen, sodium, potassium, and phosphorus; increases protein anabolism; decreases amino acid catabolism and decreased urinary excretion of calcium. The antitumour activity of fluoxymesterone appears related to reduction or competitive inhibition of prolactin receptors or estrogen receptors or production.

Androgens are highly lipid-soluble and enter cells of target tissues by passive diffusion. Testosterone or 5-alpha-dihydrotestosterone (DHT), a metabolite produced from testosterone by the enzyme 5-alpha-reductase, binds to an intracellular androgen receptor. The hormone receptor complex translocates into the nucleus and attaches to specific hormone receptor elements on the chromosome to initiate or suppress transcription and protein synthesis. Testosterone can produce estrogenic effects as a result of its conversion to estrogen. /Androgens/

Exogenous administration of androgens inhibits the release of endogenous testosterone via feedback inhibition of pituitary luteinizing hormone (LH). Following administration of large doses of exogenous androgens, spermatogenesis also may be suppressed as a result of feedback inhibition of pituitary follicle-stimulating hormone (FSH). Androgens reportedly stimulate the production of erythrocytes, apparently by enhancing the production of erythropoietic stimulating factor. /Androgens/

9.2 hours

Approximately 9.2 hours

Presence of 17-alpha alkyl group reduces susceptibility to hepatic enzyme degradation, which slows metabolism and allows oral administration. Inactivation of testosterone occurs primarily in the liver

Presence of 17-alpha alkyl group reduces susceptibility to hepatic enzyme degradation, which slows metabolism and allows oral administration.

Presence of 17-alpha alkyl group reduces susceptibility to hepatic enzyme degradation, which slows metabolism and allows oral administration. Inactivation of testosterone occurs primarily in the liver Half Life: 9.2 hours

9JU12S4YFY

FLUOXYMESTERONE

Established Pharmacologic Class [EPC] - Androgen

Mechanisms of Action [MoA] - Androgen Receptor Agonists

Chemical Structure [CS] - Androstanes

Fluoxymesterone is an Androgen. The mechanism of action of fluoxymesterone is as an Androgen Receptor Agonist.

Oral absorption is less than 44%.

It is not known whether fluoxymesterone is distributed into milk.

Less than 5% is excreted in urine as free steroid and glucuronide conjugate over a 24 hour period after doses of 20 to 200 mg.

MEDICATION

In males, used as replacement therapy in conditions associated with symptoms of deficiency or absence of endogenous testosterone. In females, for palliation of androgenresponsive recurrent mammary cancer in women who are more than one year but less than five years postmenopausal.

PREPARATION ... CF HERR, US PATENT 2813881 (1957 TO UPJOHN).

From 17-methyltestosterone first by introduction of hydroxyl group at position 11 through oxidation with microorganism (such as pestalotia or aspergillus), followed by dehydration, epoxidation & treatment with mercury ...

Prepared from 17-alpha-methyltestosterone by conversion into the 11-alpha- hydroxy derivative by microbiological oxidation with Rhizopus; tosylation at C-11, followed by elimination ... yields the 9,11-ene; addition of hypobromous acid ... /yields/ the 9-beta, 11-beta-epoxide; hydrogen fluoride fission of the epoxide ring yields fluoxymesterone

Oral: Tablets: 10 mg Fluoxymesterone Tablets (C-III), (Upsher-Smith).

Tablets, USP; 2 mg, 5 mg and 10 mg

While data specific to fluosymestrone were not located(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

This is a controlled substance (anabolic steroid)... .

Anabolic Steroid Control Act of 2004. Public Law 108-358 (October 22, 2004)... includes /fluoxymesterone/ as an anabolic steroid