Tamoxifen citrate

Iupac Name：2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid

Molecular Weight：563.647

Modify Date.: 2022-11-05 04:35

Introduction: Tamoxifen, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine(Nolvadex), is a triphenylethylene SERM used to treatearly and advanced breast carcinoma in postmenopausalwomen. Tamoxifen is used as adjuvant treatment for breastcancer in women following mastectomy and breast irradiation.It reduces the occurrence of contralateral breast cancerin patients receiving adjuvant tamoxifen therapy. It is alsoeffective in the treatment of metastatic breast cancer in bothwomen and men. In premenopausal women with metastaticbreast cancer, tamoxifen is an alternative to oophorectomyor ovarian irradiation. Tamoxifen can be used preventativelyto reduce the incidence of breast cancer in women athigh risk. Antiestrogenic and estrogenic side effects caninclude hot flashes, nausea, vomiting, platelet reduction,and (in patients with bone metastases) hypercalcemia. Likeall triphenylethylene derivatives, it should be protectedfrom light.The major metabolite of tamoxifen is N-desmethyltamoxifen,which reaches steady-state levels higher than tamoxifenitself. It is believed that N-desmethyltamoxifen contributessignificantly to the overall antiestrogenic effect. Anothermetabolite, 4-hydroxytamoxifen, is a more potent antiestrogenthan tamoxifen, but because it is only a minor metaboliteof tamoxifen, it probably does not contribute significantly tothe therapeutic effects. 4-Hydroxytamoxifen, with its greateraffinity for the ERs, however, has been used extensively inpharmacological studies of these receptors. Tamoxifen concentrationsare reduced if coadministered with rifampin, a cytochromeP450 inducer. View more+

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1. Names and Identifiers

1.1 Name: Tamoxifen citrate
1.2 Synonyms: (Z)-[2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl]dimethylammonium dihydrogen 2-hydroxypropane-1,2,3-tricarboxylate (Z)-1-(4-Dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene Citrate (Z)-2-(4-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylethanamine, citrate (1:1) 2-{4-[(1Z)-1,2-Diphenyl-1-buten-1-yl]phenoxy}-N,N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate (1:1) 2-{4-[(1Z)-1,2-Diphenylbut-1-en-1-yl]phenoxy}-N,N-dimethylethanamine 2-hydroxypropane-1,2,3-tricarboxylate (1:1) 2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}-N,N-dimethylethanamine 2-hydroxypropane-1,2,3-tricarboxylate (salt) 2-{4-[(1Z)-1,2-Diphenylbut-1-en-1-yl]phenoxy}-N,N-dimethylethanaminium hydrogen 2-hydroxypropane-1,2,3-tricarboxylate (1:2:1) 2YR&UYR&R DO2N1&1 &&Z Form citrate EINECS 259-415-2 Ethanamine, 2-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]-N,N-dimethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) (salt) Ethanamine, 2-4-(1Z)-1,2-diphenyl-1-butenylphenoxy-N,N-dimethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) MFCD00058321 Tamoxifen (Citrate) TAMOXIFEN CITRATE ANTI-ESTROGEN, PROTEI Tamoxifen citrate salt Tamoxifen, citrate salt TAMOXIFENCITRATE,USP TAMOXIPHEN TomixipheneCitrate trans-2-(p-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylethylamine citrate

1.3 CAS No.: 54965-24-1

1.4 CID: 2733525

1.5 EINECS(EC#): 259-415-2

1.6 Molecular Formula: C32H37NO8 (isomer)

1.7 Inchi: InChI=1S/C26H29NO.C6H8O7/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3;7-3(8)1-6(13,5(11)12)2-4(9)10/h5-18H,4,19-20H2,1-3H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b26-25-;

1.8 InChkey: FQZYTYWMLGAPFJ-OQKDUQJOSA-N

1.9 Canonical Smiles: CCC(=C(C1=CC=CC=C1)C2=CC=C(C=C2)OCCN(C)C)C3=CC=CC=C3.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

1.10 Isomers Smiles: CC/C(=C(\C1=CC=CC=C1)/C2=CC=C(C=C2)OCCN(C)C)/C3=CC=CC=C3.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

2. Properties

2.1 Melting point: 140-144℃

2.1 Boiling point: 665.9 °C at 760 mmHg

2.1 Flash Point: 356.5 °C

2.1 Precise Quality: 563.25200

2.1 PSA: 144.60000

2.1 logP: 4.74760

2.1 Solubility: methanol: soluble50mg/mL, clear, colorless

2.2 Appearance: white to off-white powder

2.3 Storage: Keep Cold. Hygroscopic. Light Sensitive.

2.4 Chemical Properties: white to off-white powder

2.5 Color/Form: Crystals from petroleum ether.

2.6 Water Solubility: slightly soluble

2.7 Stability: Stable under normal temperatures and pressures.

2.8 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 General Description: Tamoxifen, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine(Nolvadex), is a triphenylethylene SERM used to treatearly and advanced breast carcinoma in postmenopausalwomen. Tamoxifen is used as adjuvant treatment for breastcancer in women following mastectomy and breast irradiation.It reduces the occurrence of contralateral breast cancerin patients receiving adjuvant tamoxifen therapy. It is alsoeffective in the treatment of metastatic breast cancer in bothwomen and men. In premenopausal women with metastaticbreast cancer, tamoxifen is an alternative to oophorectomyor ovarian irradiation. Tamoxifen can be used preventativelyto reduce the incidence of breast cancer in women athigh risk. Antiestrogenic and estrogenic side effects caninclude hot flashes, nausea, vomiting, platelet reduction,and (in patients with bone metastases) hypercalcemia. Likeall triphenylethylene derivatives, it should be protectedfrom light.The major metabolite of tamoxifen is N-desmethyltamoxifen,which reaches steady-state levels higher than tamoxifenitself. It is believed that N-desmethyltamoxifen contributessignificantly to the overall antiestrogenic effect. Anothermetabolite, 4-hydroxytamoxifen, is a more potent antiestrogenthan tamoxifen, but because it is only a minor metaboliteof tamoxifen, it probably does not contribute significantly tothe therapeutic effects. 4-Hydroxytamoxifen, with its greateraffinity for the ERs, however, has been used extensively inpharmacological studies of these receptors. Tamoxifen concentrationsare reduced if coadministered with rifampin, a cytochromeP450 inducer.

3.2 GHS Classification: Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 55 companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (96.36%): Harmful if swallowed [Warning Acute toxicity, oral]
H350 (96.36%): May cause cancer [Danger Carcinogenicity]
H360 (94.55%): May damage fertility or the unborn child [Danger Reproductive toxicity]
H362 (43.64%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]
H400 (10.91%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410 (16.36%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P260, P263, P264, P270, P273, P281, P301+P312, P308+P313, P330, P391, P405, and P501

3.3 Usage: estrogen antagonist, antineoplastic

4. Safety and Handling

4.1 Symbol: GHS07;GHS08;

4.1 Hazard Codes: T

4.1 Signal Word: DANGER

4.1 Risk Statements: R22;R45

4.1 Safety Statements: S45;S53

4.1 Exposure Standards and Regulations: The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tamoxifen citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /tamoxifen citrate/

4.2 Octanol/Water Partition Coefficient: log Kow = 6.30 (est)

4.3 Other Preventative Measures: /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Appropriate engineering controls should be in place to protect the drug product from microbial contamination and to protect personnel and the environment from the potential hazards of the product. These engineering controls should be maintained according to applicable regulations and standards. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Biological safety cabinets should be cleaned and disinfected regularly to ensure a proper environment for preparation of sterile products. For routine cleanups of surfaces between decontaminations, water should be used (for injection or irrigation) with or without a small amount of cleaner. If the contamination is soluble only in alcohol, then 70% isopropyl or ethyl alcohol may be used in addition to the cleaner. In general, alcohol is not a good cleaner, only a disinfectant, and its use in a biohazard cabinet should be limited. The biohazard cabinet should be disinfected with 70% alcohol before any aseptic manipulation is begun. The excessive use of alcohol should be avoided in biohazard cabinets where air is recirculated ... because alcohol vapors may build up in the cabinet. A lint-free, plastic-backed disposable liner may be used in the biological safety cabinet to facilitate spill cleanup. ... If used, the liner should be changed frequently ... /or/ whenever it is overtly contaminated. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The biological safety cabinets should be decontaminated on a regular basis (ideally at least weekly) and whenever there is a spill or the biological safety cabinet is moved or serviced, including for certification. ... Currently, no single reagent will deactivate all known hazardous drugs; therefore, decontamination of a biological safety cabinet used for such drugs is limited to removal of contamination from a nondisposable surface (the cabinet) to a disposable surface (eg, gauze or towels) by use of a good cleaning agent that removes chemicals from stainless steel. The cleaning agent selected should have a pH approximating that of soap and be appropriate for stainless steel. Cleaners containing chemicals such as quaternary ammonium compounds should be used with caution, because they may be hazardous to humans and their vapors may build up in any biological safety cabinet where air is recirculated. Similar caution should be used with any pressurized aerosol cleaner; spraying a pressurized aerosol into a biological safety cabinet may disrupt the protective containment airflow, damage the high efficiency particulate air filter, and cause an accumulation of the propellant within a biological safety cabinet where air is recirculated, resulting in a fire and explosion hazard. During decontamination, the operator should wear a disposable closed front gown, disposable latex gloves covered by disposable utility gloves, safety glasses or goggles, a hair covering, and a disposable respirator, because the glass shield of the biological safety cabinet occasionally must be lifted. The blower must be left on, and only heavy toweling or gauze should be used in the biological safety cabinet to prevent it from being "sucked" up the plenum and into the high efficiency particulate air filter. Decontamination should be done from top to bottom (areas of lesser contamination to greater) by applying the cleaner, scrubbing, and rinsing thoroughly with distilled or deionized water. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The high efficiency particulate air filters /or other exhaust scrubbing system/ of the biohazard cabinet must be replaced whenever they restrict required airflow velocity or if they are overtly contaminated (eg, by a breach in technique that causes hazardous drug to be introduced onto the clean side of the supply high efficiency particulate air filter). Personnel and environmental protection must be maintained during replacement of a contaminated high efficiency particulate air filter. Because replacement of a high efficiency particulate air filter generally requires breaking the integrity of the containment aspect of the cabinet, this procedure may release contamination from the filter into the pharmacy or intravenous preparation area if carried out in an inappropriate manner. Before replacement of a high efficiency particulate air filter contaminated with hazardous drugs, the biological safety cabinet service agent should be consulted for a mutually acceptable procedure for replacing and subsequently disposing of a contaminated high efficiency particulate air filter. One procedure would include moving the biological safety cabinet to a secluded area or using plastic barriers to segregate the contaminated area. Protective clothing and equipment must be used by the servicer. The biological safety cabinet should be decontaminated before filter replacement. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During removal of gloves, ... avoid touching the inside of the glove or the skin with the contaminated glove fingers. ... The worker should wear a protective disposable gown made of lint free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous drugs. Washable garments are immediately penetrated by liquids and therefore provide little, if any protection. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When double gloving, one glove should be placed under the gown cuff and one over. The glove-gown interface should be such that no skin on the arm or wrist is exposed. Gloves and gowns should not be worn outside the immediate preparation area. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Eyewash fountains should be available in areas where hazardous drugs are routinely handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Although noninjectable dosage forms of hazardous drugs contain varying proportions of drug to nondrug (nonhazardous) components, there is potential for personnel exposure and environmental contamination with the hazardous components. Procedures should be developed to avoid the release of aerosolized powder or liquid into the environment during manipulation of these drugs. Drugs designated as hazardous should be labeled or otherwise identified as such to prevent their improper handling. Tablet and capsule forms of these drugs should not be placed in automated counting machines, which subject them to stress and may introduce powdered contaminants into the work area. During routine handling of hazardous drugs and contaminated equipment, workers should wear one pair of gloves of good quality and thickness. The counting and pouring of hazardous drugs should be done carefully, and clean equipment dedicated for use with these drugs should be used. ... When hazardous drug tablets in unit-of-use packaging are being crushed, the package should be placed in a small sealable plastic bag and crushed with a spoon or pestle; caution should be used not to break the plastic bag. Disposal of unused or unusable oral or topical dosage forms of hazardous drugs should be performed in the same manner as for hazardous injectable dosage forms and waste. ... Hazardous drug work areas should have a sink (preferably with an eyewash fountain) and appropriate first aid equipment to treat accidental skin or eye contact according to the protocol. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A distinctive warning label with an appropriate CAUTION statement should be attached to all hazardous drug materials, consistent with state laws and regulations. This would include, for example, syringes, IV containers, containers of unit-dose tablets and liquids, prescription vials and bottles, waste containers, and patient specimens that contain hazardous drugs. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Supplies of disposable gloves and gowns, safety glasses, disposable plastic-backed absorbent liners, gauze pads, hazardous waste disposal bags, hazardous drug warning labels, and puncture-resistant containers for disposal of needles and ampuls should be conveniently located for all areas where hazardous drugs are handled. Assembling a "hazardous drug preparation and administration kit" is one way to furnish nursing and medical personnel with the materials needed to reduce the risk of preparing and administering a hazardous drug. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Prospective temporary and permanent employees who may be required to work with hazardous drugs should be so notified and should receive adequate information about the policies and procedures pertaining to their use. This notification should be documented during the interview process and retained as part of the employment record for all employees. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All personnel involved with the transportation, preparation, administration, and disposal of cytotoxic and hazardous substances should continually be updated on new or revised information on safe handling of cytotoxic and hazardous substances. Policies and procedures should be updated accordingly. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The work area should be designed to provide easy access to those items necessary to prepare, label, and transport final products; contain all related waste; and avoid inadvertent contamination of the work area. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each health-care setting should have an established first aid protocol for treating cases of direct contact with hazardous drugs, many of which are irritating or caustic and can cause tissue destruction. Medical care providers in each setting should be contacted for input into this protocol. The protocol should include immediate treatment measures and should specify the type and location of medical follow-up and work-injury reporting. Copies of the protocol, highlighting emergency measures, should be posted wherever hazardous drugs are routinely handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only individuals trained to administer hazardous drugs should be allowed to perform this function. Training programs should contain information on the therapeutic and adverse effects of these drugs and the potential, long term health risk to personnel handling these drugs. Each individual's knowledge and technique should be evaluated before administration of these drugs. This should be done by written examination and direct observation of the individual's performance. /Antineoplastic agents/

4.4 Hazard Class: IRRITANT

4.4 Hazard Declaration: H302; H350; H360

4.4 Cleanup Methods: /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

4.5 DisposalMethods: SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The gown should be removed and placed in a sealable container before removal of the inner gloves. The inner gloves should be removed last and placed in the container with the gown. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Hazardous drug waste should be placed in specially marked (specifically labeled CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. These receptacles should be kept in all areas where the drugs are commonly used. All and only hazardous drug waste should be placed in them. Receptacles used for glass fragments, needles, and syringes should be puncture resistant. Hazardous drug waste should not be mixed with any other waste. Waste containers should be handled with uncontaminated gloves. ... Gloves, gowns, drug vials, etc, should be sealed in specially labeled (CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. ... All hazardous waste collected from drug preparation and patient-care areas should be held in a secure place in labeled, leakproof drums or cartons (as required by state or local regulation or disposal contractor) until disposal. This waste should be disposed of as hazardous or toxic waste in an EPA-permitted state-licensed hazardous waste incinerator. Transport to an offsite incinerator should be done by a contractor licensed to handle and transport hazardous waste. ... If access to an appropriately licensed incinerator is not available, transport to and burial in an EPA-licensed hazardous waste dump site is an acceptable alternative. While there are concerns that destruction of carcinogens by incineration may be incomplete, newer technologies and stringent licensing criteria have improved this disposal method. ... Chemical deactivation of hazardous drugs should be undertaken only by individuals who are thoroughly familiar with the chemicals and the procedures required to complete such a task. The IARC recently published a monograph describing methods for chemical destruction of some cytotoxic (antineoplastic) drugs in the laboratory setting. The chemicals and equipment described, however, are not generally found in the clinical setting, and many of the deactivating chemicals are toxic and hazardous. Most procedures require the use of a chemical fume hood. The procedures are generally difficult, and the deactivation is not always complete. Serious consideration should be given to the negative aspects of chemical deactivation before one commits to such a course of action. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Regulatory agencies such as the EPA and state solid and hazardous waste agencies and local air and water quality control boards must be consulted regarding the classification and appropriate disposal of drugs that are defined as hazardous or toxic chemicals. EPA categorizes several of the antineoplastic agents as toxic wastes, while many states are more stringent and include as carcinogens certain cytotoxic drugs and hormonal preparations. EPA also allows exemptions from toxic waste regulations for small quantity generators, whereas certain states do not. It is critical to research these regulations when disposal procedures are being established. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If the biological safety cabinets is equipped with a drainpipe and valve, it may be used to collect rinse water. The collection vessel used must fit well around the drain valve and not allow splashing. Gauze may be used around the connection to prevent aerosol from escaping. The collection vessel must have a tight fitting cover, and all rinse water (gauze, if used) must be disposed of as contaminated waste. /Antineoplastic agents/

4.6 RIDADR: UN 3077 9 / PGIII

4.6 Safety Profile: Confirmed human carcinogen with experimental carcinogenic data. Poison by intraperitoneal route. Moderately toxic by ingestion. Experimental reproductive effects. Human systemic effects: visual field changes, retinal changes. An anti-estrogenic drug. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx. Tamoxifen citrate Preparation Products And Raw materials Raw materials

4.7 Caution Statement: P201-P280-P301 + P312 + P330-P308 + P313

4.7 WGK Germany: 3

4.7 RTECS: KH2387000

4.7 Protective Equipment and Clothing: /PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

4.8 Report: IARC Cancer Review: Human Sufficient Evidence (Benefits outweigh risk for breast cancer patients. 22 Feb, 1997).

4.9 Safety: Confirmed human carcinogen with experimental carcinogenic data. Poison by intraperitoneal route. Moderately toxic by ingestion. Experimental reproductive effects. Human systemic effects: visual field changes, retinal changes. An anti-estrogenic drug. Mutation data reported. When heated to decomposition it emits toxic fumes of NO_x.
Hazard Codes:?T,Xi
Risk Statements: 45-60-61-22-64-36/37/38?
R45:May cause cancer.?
R60:May impair fertility.?
R61:May cause harm to the unborn child.?
R22:Harmful if swallowed.?
R64:May cause harm to breastfed babies.?
R36/37/38:Irritating to eyes, respiratory system and skin.
Safety Statements: 53-36/37/39-45-36-26?
S53:Avoid exposure - obtain special instructions before use.?
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection.?
S45:In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)?
S36:Wear suitable protective clothing.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
WGK Germany: 3
RTECS: KH2387000

4.10 Specification: ?Tamoxifen citrate , its cas register number 54965-24-1. It also can be called?(Z)-2-(p-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylethylamine citrate (1:1) ; Apo-Tamox ; Caditam ;
Emblon ; Ethanamine, 2-(4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) ; Farmifeno ; Genox ; Ginarsan ; ICI 46,474 ; ICI 46474 ; Jenoxifen ; Kessar ; Ledertam ; NSC 180973 ; Nolgen ; Noltam ; Nolvadex ; Nourytan ; Noxitem ; Oncotam ; Soltamox ; TMX ; Tafoxen ; Tamax ; Tamofen ; Tamoplex ; Tamox-Puren ; Tamoxasta ; Tamoxifen citrate ; Taxus ; Terimon ; UNII-7FRV7310N6 ; Z-Tamoxifen citrate ; Zemide ; Zitazonium ; Zynoplex ; and trans-1-(p-beta -Dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene citrate .?Its classification code are?Anti-estrogen; Drug / Therapeutic Agent;?Human Data;?Mutation data;?Reproductive Effect and Tumor data.
?Tamoxifen citrate (CAS NO.54965-24-1) could be stable under normal temperatures and pressures. It should avoid the condition like incompatible materials, light, heat. It is not compatible with strong oxidizing agents. And also prevent it to broken down into hazardous decomposition products: Nitrogen oxides, carbon monoxide, carbon dioxide. However, its hazardous polymerization will not occur.

4.11 Toxicity

1.	???	add-rat-ipr 60?mg/kg/3D-C	???	CNREA8 ?? Cancer Research. 52 (1992),1360.
2.	???	add-ham-ipr 10?mg/kg	???	CNREA8 ?? Cancer Research. 52 (1992),1360.
3.	???	orl-rat TDLo:15,512?mg/kg/1Y-I:CAR	???	CRNGDP ?? Carcinogenesis. 14 (1993),315.
4.	???	orl-wmn TDLo:154?mg/kg/1Y-I:EYE	???	AJOPAA ?? American Journal of Ophthalmology. 104 (1987),185.
5.	???	orl-rat LD50:1190?mg/kg	???	JZKEDZ ?? Jitchuken, Zenrinsho Kenkyuho. Central Institute for Experimental Animals, Preclinical Reports. 6 (1980),1.
6.	???	ipr-rat LD50:575?mg/kg	???	JZKEDZ ?? Jitchuken, Zenrinsho Kenkyuho. Central Institute for Experimental Animals, Preclinical Reports. 6 (1980),1.
7.	???	orl-mus LD50:3100?mg/kg	???	JRPFA4 ?? Journal of Reproduction and Fertility. 13 (1967),101.
8.	???	ipr-mus LD50:218?mg/kg	???	NIIRDN ?? “Drugs in Japan. Ethical Drugs, 6th Edition 1982“ Edited by Japan Pharmaceutical Information Center. 6 (1982),440.

?Tamoxifen citrate (CAS NO.54965-24-1) has been listed as a carcinogen by? IARC: Group 1 carcinogen .It may cause neurotoxic effects. See actual entry in RTECS for complete information. The toxicological properties have not been fully investigated.

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5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

Carcinogenicity, Category 1B

Reproductive toxicity, Category 1B

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H302 Harmful if swallowed H350 May cause cancer H360 May damage fertility or the unborn child
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth. P308+P313 IF exposed or concerned: Get medical advice/ attention.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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6. NMR Spectrum

Predict 1H proton NMR

7. Synthesis Route

54965-24-1Total: 1 Synthesis Route

10540-29-1 186 Suppliers

77-92-9 1380 Suppliers

54965-24-1 464 Suppliers

Literatures:
Pharmaceutical Research, , vol. 23, # 4 p. 806 - 812
Yield: null

8. Precursor and Product

precursor:

77-92-9

10540-29-1

9. Other Information

9.0 Merck: 14,9048

9.1 Overview: Tamoxifen, sold under the brand name Nolvadex among others, is a medication that is used to prevent breast cancer in women and treat breast cancer in women and men. The introduction of the anti-oestrogen tamoxifen in the early 1970s represented a landmark in the treatment of breast cancer. Over 40 years later, tamoxifen has been shown to be effective not only for early and advanced breast cancer, but also for ductal carcinoma in situ (DCIS) and the chemoprevention of breast cancer in high-risk pre- and post- menopausal women. Indeed, tamoxifen is the benchmark against which newer endocrine therapies continue to be measured.
Breast cancer is the second highly pervasive cause of mortalities in the world^[1]. It does not cover only women but also men and food animals. Metastatic breast cancer is more drastic as the main causative agent is not known. Although, multiple causes have been known to be involved in the metastatic breast cancer, but still chemotherapy is a question to absolutely treat this cancer^[1]. 1.3 million women suffer from breast cancer in United States. Similarly 1 out of every 7 women had breast cancer. Not only humans but also animals become victim of breast cancer. Tamoxifen was introduced by AstraZeneca of UK for the first time and being frequently prescribed as hormonal therapy for estrogen positive breast cancer in the clinics of Pakistan and Australia. It is far better to use right medicine with right dose at the right stage of the disease to opt maximum curative results. The exact kinetic and dynamic mechanism within human is necessary for manufacturing a drug against any disease.

Figure 1 the chemical structure of Tamoxifen

9.2 Application: Long term use of Tamoxifen as prophylaxis is recommended and found useful with decrease in recurrence rate of breast cancer. The risk-lowering effect of Tamoxifen appears to persist for at least 10 years, yet most side effects of Tamoxifen do not continue after the 5-year treatment period. Thus the long term treatment with Tamoxifen is appreciated^[4]. Tamoxifen has been the adjuvant therapy of choice for postmenopausal, node-positive, and estrogen or progesterone receptor positive women since the mid-1980s, and for postmenopausal, node-negative, and estrogen or progesterone receptor-positive women since the early 1990s. It is also being used in many cases of node-negative and receptor-positive premenopausal women. A high proportion (40-60%) of all women who undergo potentially curative surgery for breast cancer now receive adjuvant Tamoxifen therapy for a period of 2 to 5 years. It was first approved for pharmaceutical use in the United Kingdom in 1973 and in the United States in 1977; Tamoxifen is presently registered in 97 countries. Tamoxifen use has been estimated at more than 7 million patient/years. The usual dose in the United States and the United Kingdom is 20 mg/day for 1 to 2 years whereas in continental Europe, usual doses are 30 to 40 mg/day^[5].
Tamoxifen is used for the treatment of invasive breast cancer in men and women, the most common type of breast cancer, following surgery and/or radiation and for preventing invasive breast cancer in women at high risk for developing it. Tamoxifen also is used for the treatment of women following surgery and radiation for a less common type of breast cancer called ductal carcinoma in situ (DCIS or Intraductal Carcinoma). Women who have had DCIS are at high risk for developing invasive breast cancer at a later date, and tamoxifen prevents development of the invasive cancer in almost half of the women during the first five years of treatment. Occasionally, tamoxifen is used to stimulate ovulation.

9.3 Mode of action: Tamoxifen is being frequently prescribed as hormonal therapy of estrogen positive breast cancer in the clinics of Pakistan. There is a competitive binding of tamoxifen to estrogen receptors in cancer cells and other tissue targets, and this in turn produces a nuclear complex that decreases DNA synthesis and inhibits estrogen action. It is a non-steroidal agent with potential anti estrogenic abilities which occupies estrogen binding sites in breast tissue and metabolized by the liver enzyme Cyp2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6), rendering active metabolites of Tamoxifen includes N-desmethyl tamoxifen, endoxifen and 4 hydroxy tamoxifen^[2]. Tamoxifen is known as a classic pro-drug requiring metabolic activation to start its pharmacological activity. Mainly 2D6 of cytochrome 450 appears to be the rate-limiting enzyme converting the pharmacologically inactive metabolites (Tamoxifen and NDM) to endoxifen, and further contributes to the formation of 4-OH-Tam from Tamoxifen. The findings depict that both genetic and environmental (drug-induced) factors that change CYP2D6 enzyme activity affect Tamoxifen treatment results^[2]. Research was done to check the breast density after use of Tamoxifen in patients. MRI of breast was performed after Tamoxifen use. It was concluded that with the use of Tamoxifen breast cancer is reduced hence the breast density came out to be less^[3].

9.4 Pharmacodynamics: The excretory fate of Tamoxifen and its metabolites has not been well characterized. Following oral administration of 20 mg dose of radio labeled Tamoxifen in women, normally 65% of the administered dose was excreted in feces for a 2-week time period, mainly as polar conjugates; unchanged tamoxifen and unconjugated metabolites accounted for less than 30% of the fecal radioactivity. Unchanged tamoxifen and N-desmethyl tamoxifen have been detected in urine in small amounts. In animals, Tamoxifen and/or its metabolites appear to undergo extensive enterohepatic circulation and are excreted in feces and urine as glucuronides, other conjugates, and unidentified polar metabolites^[6]. In a study involving six healthy male volunteers, Tamoxifen tablets were shown to be as bioavailable as a solution of Tamoxifen citrate. After administration of a single dose of 20 mg, peak serum levels of Tamoxifen were 42 ng/ml; those of the metabolite were 12 ng/ml. The half-lives of the drug and metabolite were approximately 4 and 9 days, respectively, after a single dose. After three widely separated single doses, a reversible increase in elimination half-life occurred^[7]. Tamoxifen is extensively metabolised after oral administration. N-desmethyl Tamoxifen, the major metabolite found in patients’ plasma, undergoes secondary metabolism to 4-hydroxy-N-desmethyl Tamoxifen (endoxifen). The enzyme involved in this conversion is cytochrome P450 2D6 (CYP2D6), which also converts Tamoxifen to 4-hydroxy Tamoxifen. This metabolite undergoes secondary metabolism to endoxifen. It is widely accepted that the majority of the anti-proliferative effect of Tamoxifen occurs via its active metabolites. 4-hydroxy Tamoxifen has at least 100-fold greater affinity for the ER than Tamoxifen, and has a similarly increased potency in anti-proliferative action. Endoxifen has an equivalent anti-proliferative potency and ER binding ability to 4-hydroxy Tamoxifen but is present in higher concentrations in the plasma. Any factor that diminishes production of these metabolites could impact on Tamoxifen efficacy. Several enzymes are involved in these metabolic pathways, with CYP2D6 playing a pivotal role. CYP2D6 is a polymorphic gene with over 90 documented alleles^[8].
Peak concentrations occur 4-7 h after oral dosing. Peak concentrations after single oral doses of 20mg are about 40μg/l. There is no information on absolute bioavailability^[10-12]. The elimination is biphasic, with an initial half-life of around 7 h and a terminal half-life of 7-11 days^[8-10]. Tamoxifen is more than 99% protein-bound in serum, predominantly to albumin. In patients with breast cancer, concentrations of Tamoxifen and its metabolites in pleural, pericardial and peritoneal effusion fluid are between 20 and 100% of those in serum, but only trace amounts enter the cerebrospinal fluid. Concentrations in breast cancer tissue exceed those in serum. The volume of distribution is 50-60 l/kg^[11,12].

9.5 Side effects: Most common side effects caused by tamoxifen are nausea, hot flashes, vaginal dryness, loss of sexual desire. It is notable that tamoxifen is not an antagonist at all tissues like in breast tissue. It therefore has agonist effect in bones and ovaries. In addition, it does not have a cardioprotective effect on heart and causes thromboembolism and fatty liver. It shows a reduction in libido and evidences of decreased cognition have been reported. The side effect of tamoxifen at mitochondrial level lies in an increased reactive oxygen species pathway due to tamoxifen within mitochondria of a cell leading to apoptosis^[13]. Whilst it may also prove that the tamoxifen may leads to aging process as it is being used by breast cancer patients for more than 5 years. Less common side effects include anxiety, blistering, peeling, or loosening of the skin and mucous membranes, blurred vision, cataracts in the eyes or other eye problems, change in vaginal discharge, chest pain, chills, confusion, cough, dizziness, fainting, fast heartbeat, fever, hoarseness, lightheadedness, lower back or side pain, pain or feeling of pressure in the pelvis, pain or swelling in the legs, pain, redness, or swelling in your arm or leg, painful or difficult urination, rapid shallow breathing, shortness of breath or trouble with breathing, skin rash or itching over the entire body, sweating, weakness or sleepiness, wheezing, vaginal bleeding and yellow eyes or skin. More common side effects are absent, missed, or irregular periods and decrease in the amount of urine. There seems to be correlation between long-term Tamoxifen administration and endometrial proliferation^[14]. Mild-moderate gastrointestinal toxicity (diarrhea, anorexia) and reversible neurotoxicity were observed in dogs receiving chemotherapy plus high-dose Tamoxifen given for seven days^[15]. Nausea and vomiting can occur. Dizziness, lethargy, depression, irritability and cerebellar dysfunction have been described.

9.6 References

Shahbaz K, Mehfooz A, Khadam W, Din MU, Shahbaz K, et al. (2014) Breast Cancer Vaccination- An Envisioned Future. IAJPR 4(3): 1580-1585.
Fuchs WS, Leary WP, van der MMJ, Gay S, Witschital K, et al. (1996) Pharmacokinetics and Bioavailability of Tamoxifen in Postmenopausal healthy women. Arzneimittelforschung 46(4): 418-422.
Chen JH, Yeun CC, Daniel C, Yi TW, Ke N, et al. (2011) Reduction of breast density using tamoxifen treatment evaluated by 3D MRI. Magon reson imaging 29(1): 91-98.
Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, et al. (2007) Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer 96-Month Follow-up of the Randomized IBIS-I Trial. J Natl Cancer Inst 99(4): 272-282.
Guelen P, Stevenson D, Briggs R, De Vos D (1987) The bioavailability of Tamoplex (tamoxifen). Part 2. A single dose cross-over study in healthy male volunteers. Methods Find Exp Clin Pharmacol 9(10): 685-90.
De Santana DP, Rossana MCB, Ruth S, Miracy MA, César GB, et al. (2008) Reversed phase HPLC determination of Tamoxifen in dog plasma and its pharmacokinetic after a single oral dose administration. Quim Nova 31(1): 47-52. 21.
Adam HK, Patterson JS, Kemp JV (1980) Studies in the metabolism and pharmacokinetics of Tamoxifen in normal volunteers. Cancer Treat Rep 64(6-7): 761-764.
Golander Y, Sternson LA (1980) Paired-ion chromatographic analysis of Tamoxifen and two major metabolites in plasma. J Chromatogr 181(1): 41-49.
Carter SJ, Li XF, Mackey JR, Modi S, Hanson J et al. (2001) Biomonitoring of Urinary Tamoxifen and its metabolites from breast cancer patients using non-aqueous capillary electrophoresis with electrospray mass spectrometry. Electrophoresis 22(13): 2730-2706.
Martindale (1999) The Complete Drug Reference (33rd edn), Pharmaceutical Press, London, pp: 2315.
Buckley MMT, Goa KL (1989) Tamoxifen. Drugs 37(4): 451-490.
Lien EA, E Solheim, OA Lea, S Lundgren, S Kvinnsland, PM Ueland (1989) Distribution of 4-hydroxy-N-desmethylTamoxifen and other Tamoxifen metabolites in human biological fluids during Tamoxifen treatment. Cancer Res 49(8): 2175-2183.
Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, et al. (2007) Tamoxifen Induces Oxidative Stress and Mitochondrial Apoptosis via Stimulating Mitochondrial Nitric Oxide Synthase. Cancer Res 67(3): 1282-1290.
Uziely B, Lewin A, Brufman G, Dorembus D, Mor-Yosef S (1993) The effect of tamoxifen on the endometrium. Breast Cancer Res Treat 26(1): 101-105. 15. Waddle J, Fine R, Case B, Trogdon M, Tyczkowska K, et al. (1999) Phase I and pharmacokinetic analysis of high-dose tamoxifen and chemotherapy in normal and tumor-bearing dogs. Cancer Chemother Pharmacol 44(1): 74

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9.7 Chemical Properties: white to off-white powder

9.8 Originator: Nolvadex,I.C.I.,UK,1973

9.9 Uses: estrogen antagonist, antineoplastic

9.10 Uses: anti-estrogen, protein kinase C inhibitor, beneficial cardiovascular effects, bone cancer treatment, induces DNA adduct formation

9.11 Uses: Tamoxifen Citrate is a selective estrogen response modifier (SERM), protein kinase C inhibitor and anti-angiogenetic factor. Tamoxifen is a prodrug that is metabolized to active metabolites 4-hydroxytamoxifen (4-OHT) and endoxifen by cytochrome P450 isoforms CYP2D6 and CYP3A4.

9.12 Manufacturing Process: To the Grignard reagent prepared from 0.59 part of magnesium, 3.95 parts of bromobenzene and 50 parts of ether there are added 7.5 parts of 4-(β- dimethylaminoethoxy)-α-ethyldesoxybenzoin in 50 parts of ether. After heating under reflux for 3 hours, the mixture is decomposed by the addition of a solution of 60 parts of ammonium chloride in 150 parts of water. The mixture is separated, and the ethereal layer is dried with anhydrous sodium sulfate, and the ether is evaporated. The residue is crystallized from methanol. There is thus obtained 1-(p-β-dimethylaminoethoxyphenyl)-1,2- diphenylbutan-1-ol, melting point 120°C to 121°C.
2.15 parts of 1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbutan-1-ol, 25 parts of ethanol and 0.8 part of 10 N hydrochloric acid are heated together under reflux for 3 hours. The solution is evaporated to dryness under reduced pressure and the residue is extracted with methylene chloride. The methylene chloride extract is decolorized with charcoal and then evaporated to dryness. The residue is dissolved in 100 parts of water, the solution is basified by the addition of sodium hydroxide solution, and the precipitated solid is extracted three times, each time with 50 parts of ether. The combined extracts are dried with anhydrous sodium sulfate and then evaporated. The residue is crystallized from aqueous methanol, and there is thus obtained 1-(p-β- dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, melting point 95°C to 96°C.

9.13 Brand name: Nolvadex (AstraZeneca); Soltamox (Savient).

9.14 Therapeutic Function: Antiestrogen, Antineoplastic

9.15 General Description: Tamoxifen, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine(Nolvadex), is a triphenylethylene SERM used to treatearly and advanced breast carcinoma in postmenopausalwomen. Tamoxifen is used as adjuvant treatment for breastcancer in women following mastectomy and breast irradiation.It reduces the occurrence of contralateral breast cancerin patients receiving adjuvant tamoxifen therapy. It is alsoeffective in the treatment of metastatic breast cancer in bothwomen and men. In premenopausal women with metastaticbreast cancer, tamoxifen is an alternative to oophorectomyor ovarian irradiation. Tamoxifen can be used preventativelyto reduce the incidence of breast cancer in women athigh risk. Antiestrogenic and estrogenic side effects caninclude hot flashes, nausea, vomiting, platelet reduction,and (in patients with bone metastases) hypercalcemia. Likeall triphenylethylene derivatives, it should be protectedfrom light.
The major metabolite of tamoxifen is N-desmethyltamoxifen,which reaches steady-state levels higher than tamoxifenitself. It is believed that N-desmethyltamoxifen contributessignificantly to the overall antiestrogenic effect. Anothermetabolite, 4-hydroxytamoxifen, is a more potent antiestrogenthan tamoxifen, but because it is only a minor metaboliteof tamoxifen, it probably does not contribute significantly tothe therapeutic effects. 4-Hydroxytamoxifen, with its greateraffinity for the ERs, however, has been used extensively inpharmacological studies of these receptors. Tamoxifen concentrationsare reduced if coadministered with rifampin, a cytochromeP450 inducer.

9.16 Biological Activity: Estrogen receptor antagonist/partial agonist. Selective and potent inhibitor of mammalian sterol isomerase. Neuroprotective in female rats in vivo . Also high affinity agonist at the membrane estrogen receptor GPR30.

9.17 Biochem/physiol Actions: Cell permeable: yes

9.18 Safety Profile: Confirmed human carcinogen with experimental carcinogenic data. Poison by intraperitoneal route. Moderately toxic by ingestion. Experimental reproductive effects. Human systemic effects: visual field changes, retinal changes. An anti-estrogenic drug. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

9.19 Usage: Tamoxifen citrate is used as an antiestrogen with potent anti-cancer and PKC inhibitory activities. Tamoxifen Citrate functions as an estrogen receptor antagonist in breast tissue. Tamoxifen Citrate is an agonist towards this receptor in tissues of the endometrium. Tamoxifen Citrate inhibits DNA synthesis and transcription by recruiting co-repressors, which stop estrogen from interacting with genes. When combined with PAX2, Tamoxifen Citrate can inhibit the proliferation of ERBB2. It is also a high affinity activator of the GPR30 receptor. Tamoxifen Citrate is an activator of Estrogen Receptor.

10. Computational chemical data

Molecular Weight: 563.647g/mol
Molecular Formula: C₃₂H₃₇NO₈
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 563.25191714
Monoisotopic Mass: 563.25191714
Complexity: 690
Rotatable Bond Count: 13
Hydrogen Bond Donor Count: 4
Hydrogen Bond Acceptor Count: 9
Topological Polar Surface Area: 145
Heavy Atom Count: 41
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 1
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 2
CACTVS Substructure Key Fingerprint: AAADcfB+PAAAAAAAAAAAAAAAAAAAAAAAAAAwYMAAAAAAAAABUAAAHgAACAAADEThmAYyDoMABgCIAiDSCAICCAAgIAAIiAFOCIgPJjaEMRqDeCCl4BEZqAfL5uAOIAAAAAAAAABAAAAAAAAAAAAAAAAAAA==

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