Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides.
Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in plasma. N-desmethyl tamoxifen activity is similar to tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P450 CYP3A, CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein.
Tamoxifen is rapidly and extensively metabolized, principally by demethylation and to a small degree by subsequent deamination and also by hydroxylation. Initial studies suggested that 4-hydroxytamoxifen (metabolite B) was the major metabolite of the drug, but subsequent studies using improved assay methodologies have shown that 4-hydroxytamoxifen is a minor metabolite and that the major metabolite is N-desmethyltamoxifen (metabolite X). The biologic activity of N-desmethyltamoxifen appears to be similar to that of tamoxifen. N-Desmethyltamoxifen undergoes demethylation to form N,N-desdimethyltamoxifen (metabolite Z) which undergoes subsequent deamination to form the primary alcohol metabolite (metabolite Y). Both 4-hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. 3,4-Dihydroxytamoxifen and an unidentified metabolite (metabolite E) also have been detected in plasma in small amounts. With continuous administration of tamoxifen, serum concentrations of N-desmethyltamoxifen are generally about 1-2 times those of unchanged tamoxifen, while those of N,N-desdimethyltamoxifen are about 20-40% those of unchanged tamoxifen and those of the primary alcohol metabolite are about 5-25% those of unchanged tamoxifen; concentrations of the hydroxylated metabolites and metabolite E appear to be less than 5% of those of unchanged tamoxifen.
Several metabolites of tamoxifen, including 4-hydroxy-N-desmethyltamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, the primary alcohol, and N-desdimethyltamoxifen were identified and their concn determined in fluids and feces from patients receiving chronic tamoxifen treatment. The biological samples investigated were serum, pleural, pericardial and peritoneal effusions, cerebrospinal fluid, saliva, bile, feces, and urine. In serum, tamoxifen itself, and the metabolites N-desmethyltamoxifen and N-desdimethyltamoxifen were the prevailing species, but significant amounts of the metabolites the primary alcohol, 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen were also detected. About 3 hr after drug intake tamoxifen as well as, N-desmethyltamoxifen, an N-desdimethyltamoxifen) showed a peak in serum. This may be explained by efficient metabolism of the metabolite precursor before being distributed to peripheral compartments. Upon drug withdrawal all metabolites showed first-order elimination curves which paralleled that of tamoxifen suggesting that their rate of elimination exceeded that of tamoxifen and that the serum levels are production rate limited. The protein binding of tamoxifen and its major serum metabolites (the primary alcohol, N-desmethyltamoxifen, N-desdimethyltamoxifen) was determined and found to be higher than 98%. Albumin was the predominant carrier for tamoxifen in human plasma. The concn of tamoxifen and its metabolites in pleural, pericardial, and peritoneal effusions equalled those detected in serum, corresponding to an effusion/serum ratio between 0.2 and 1. Only trace amounts of tamoxifen and metabolite N-desmethyltamoxifen were detected in cerebrospinal fluid (CSF/serum ratio less than 0.02). In saliva, concn of tamoxifen and N-desmethyltamoxifen exceeded the amounts of free drug in serum, suggesting active transport or trapping of these compounds in the salivary gland. Bile and urine were rich in the hydroxylated, conjugated metabolites (the primary alcohol, 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, whereas in feces unconjugated metabolite B and tamoxifen were the predominating species.
The amount of tamoxifen, N-desmethyltamoxifen (metabolite X), N-desdimethyltamoxifen (metabolite Z), and hydroxylated metabolites (trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen) were determined in brain metastases from breast cancer patients and in the surrounding brain tissues. Specimens were collected from the breast cancer patients who received tamoxifen for 7-180 days and with the last dose taken within 28 hr before surgical removal of the tumour. The concn of tamoxifen and its metabolites were up to 46 fold higher in the brain metastatic tumour and brain tissue than in serum. Metabolite N-desmethyltamoxifen was the most abundant species followed by tamoxifen and metabolite N-desdimethyltamoxifen. Small but significant amounts of the hydroxylated metabolites, trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen were detected in most specimens. The ratios between the concn of tamoxifen and various metabolites were similar in tumour, brain and serum. This is the first report on the distribution of tamoxifen and metabolites into human brain and brain tumour, and the data form a basis for further investigation into the therapeutic effects of tamoxifen on brain metastases from breast cancer.
IDENTIFICATION: Tamoxifen is an anti-estrogenic non-steroidal drug. Indications: Treatment of advanced breast cancer and adjuvant treatment of early breast cancer. Treatment of anovulatory infertility. HUMAN EXPOSURE: Main risks and target organs: Adverse effects in therapeutic use are usually mild. They include effects caused by antagonism of endogenous oestrogens: hot flushes, non-specific gastrointestinal effects (nausea and vomiting), central nervous system effects, and rare ocular effects. Adverse hematological effects have been reported, also isolated cases of death from peliosis hepatis and from hyperlipidemia. In the treatment of breast cancer, hypercalcemia and tumor flare can occur. Summary of clinical effects: Anti-estrogenic effects in women treated with tamoxifen include vasomotor symptoms (hot flushes), vaginal bleeding and (in premenopausal women) irregular menses, and pruritus vulvae. Nausea and vomiting can occur. Dizziness, lethargy, depression, irritability and cerebellar dysfunction have been described. Reversible retinopathy with macular edema has been reported after high cumulative doses, and corneal changes can occur. Thrombocytopenia or leukopenia have been associated with tamoxifen treatment. Thromboembolism, which may be due to the disease rather than the treatment, has been recorded in women given tamoxifen for breast cancer. Contraindications: Pregnancy is an absolute contraindication because of the anti-estrogenic effects. Routes of entry: Oral: Usual route of entry Absorption by route of exposure: Peak concentrations occur 4-7 hr after oral dosing. Peak concentrations after single oral dose are about 40 u/l. Distribution by route of exposure: 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. Biological half-life by route of exposure: The elimination is biphasic, with an initial half-life of around 7 hr and a terminal half-life of 7-11 days. Metabolism: Tamoxifen citrate undergoes extensive hepatic metabolism to: 1-(4-ethanolyloxyphenyl)-1,2-diphenylbut-1-ene (the primary alcohol), N-desmethyl tamoxifen, 4-hydroxy tamoxifen, 4-hydroxy-N-desmethyl tamoxifenn and N-desdimethyl tamoxifen Elimination by route of exposure: The major excretory route is via the bile as metabolites and enterohepatic recirculation occurs. Less than 1% is excreted in the urine. Mode of action: Toxicodynamics: The adverse effects observed are due mainly to its anti-estrogen effect, as Tamoxifen and certain of its metabolites antagonise the effects of estrogens in estrogen sensitive tissues. Pharmacodynamics: Tamoxifen and several of its metabolites (particularly 4-hydroxytamoxifen) bind to nuclear estrogen receptors in estrogen sensitive tissues, and also to a microsomal protein termed the anti-estrogen binding site. Tamoxifen interferes with the physiological sequence by which estrogen binds to its receptor, is translocated in the nucleus and then activates messenger RNA synthesis. Although the tamoxifen receptor complex is transported in the nucleus in the same way as estrogen receptor complex, it fails to activate synthesis of mRNA. Carcinogenicity: A case-control study showed a significantly increased relative risk of carcinoma of the uterus in women previously treated with tamoxifen and who had previously had radiotherapy involving the uterus. The study showed an increase in relative risk with tamoxifen treatment alone which was not statistically significant. Teratogenicity: Studies in neonatal male and female mice at relative doses 10 times higher than those used in humans have shown genital tract abnormalities. Interactions: Tamoxifen potentiates the anticoagulant effect of warfarin, and this interaction can be life-threatening. Main adverse effects: Adverse effects are usually mild. Thrombocytopenia, leukopenia, thromboembolism, peliosis hepatis and hyperlipidaemia have been mentioned in case reports. Severe hypercalcemia can occur rarely when treatment is started in patients with metastases to bone. Chronic poisoning: Ingestion: Retinal damage and keratitis have been reported in patients after large cumulative doses of tamoxifen, for more than 1 year, though sometimes with smaller doses. There seems to be correlation between long term tamoxifen administration and endometrial proliferation. Neurological: CNS: A case of depression, syncope, and incoordination has been described during therapy with 10 mg twice daily. The symptoms resolved when tamoxifen was discontinued and reappeared when treatment was restarted. Gastrointestinal: Nausea and vomiting occur with therapeutic doses in some patients, and are anticipated in overdosage. Hepatic: A fatal case of peliosis hepatis has been reported in a woman treated with tamoxifen for 2 years after mastectomy for carcinoma. Urinary: Other: A case of persistent nocturnal priapism has been reported. Endocrine and reproductive systems: The anti-estrogenic effects of tamoxifen in premenopausal women receiving therapeutic doses can cause irregular menses. Anti-estrogenic adverse effects in women treated with tamoxifen include vasomotor symptoms and vaginal bleeding and pruritus vulvae. Eye, ear, nose, throat: local effects: Treatment has been associated with retinal and corneal changes. Hematological: Thromboembolism may be more common in patients treated with tamoxifen, though this is not certain, as patients with cancer are at increased risk anyway. A small reduction in antithrombin III concentration was noted in a study of 11 postmenopausal women treated with tamoxifen, but it was clinically insignificant, and no significant reduction was seen in a group of premenopausal women. Thrombocytopenia and leukopenia can occur during therapy, but are not usually severe. One case of severe myelosuppression has been reported. Fluid and electrolyte disturbances: Severe hypercalcemia, associated with increased bone resorption, has been noted when patients with bony metastases commenced therapy. Others: Severe hyperlipidemia is occasionally seen, and has been ascribed to an estrogenic effect. Special risks: Pregnancy, breast feeding and enzyme deficiencies. ANIMAL/PLANT STUDIES: In some animal species, estrogenic agonist effects become manifest at dosages equivalent to 10-100 times the human therapeutic dose. Mutagenicity: Tamoxifen is believed not to be mutagenic. /Tamoxifen citrate/
Tamoxifen is a nonsteroidal agent that binds to estrogen receptors (ER), inducing a conformational change in the receptor. This results in a blockage or change in the expression of estrogen dependent genes. The prolonged binding of tamoxifen to the nuclear chromatin of these results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. It is likely that tamoxifen interacts with other coactivators or corepressors in the tissue and binds with different estrogen receptors, ER-alpha or ER-beta, producing both estrogenic and antiestrogenic effects.
Tamoxifen has been associated with rare instances of idiosyncratic, clinically apparent liver injury, typically arising within the first six months of treatment and having variable presentations with cholestatic, mixed or hepatocellular pattern of enzyme elevations. Immunoallergic features (fever, rash, eosinophilia) are uncommon, as are autoantibodies. Some instances have been severe with signs of hepatic failure, but most cases are self-limited.
More commonly, long term tamoxifen therapy has been linked to the development of fatty liver and steatohepatitis. In some prospective studies, up to one third of women have developed fatty liver during 1 to 3 years of tamoxifen therapy, as shown by routine imaging using computerized tomography. Fatty liver usually becomes demonstrable within 1 to 2 years of starting tamoxifen but is usually not accompanied by symptoms, although serum aminotransferase levels may be elevated modestly in up to half of patients. Liver biopsy may demonstrate steatohepatitis and a proportion of women develop hepatic fibrosis. Several instances of cirrhosis have been described after therapy with tamoxifen for 3 to 5 years. Serum aminotransferase elevations and fatty liver generally improve once tamoxifen is stopped, but the improvement may be slow and in rare instances, signs and symptoms of portal hypertension persist. While the frequency of hepatic steatosis during tamoxifen therapy is higher in women with higher body weight and body mass index (BMI), the appearance of fatty liver is usually not accompanied by change in body weight and does not relate to alcohol use or receipt of adjuvant chemotherapy. Because steatohepatitis is usually (although not always) accompanied by minor serum aminotransferase elevations, monitoring of serum enzymes during long term tamoxifen therapy is often recommended.
In addition, long term tamoxifen therapy has also been linked to isolated cases of peliosis hepatis, hepatic cysts and several cases of hepatocellular carcinoma in women with no other risk factors for this tumor. However, in large retrospective analyses, no increase in hepatocellular carcinoma in women taking tamoxifen for 5 years has been demonstrated, although these same studies did show an increase in rates of endometrial carcinoma. Tamoxifen also been linked to an increased risk of venous thromboses, and instances of portal vein thrombosis with combinations of portal hypertension and esophageal variceal bleeding have been reported.
Finally, tamoxifen use has been associated with development of symptomatic porphyria cutanea tarda (PCT), presenting after 1 to 4 years of use with skin fragility, hypertrichosis and reddish urine and accompanied by elevations in urinary porphyrins and mild serum aminotransferase elevations. Tamoxifen related cases usually arise without other risk factors for PCT such as iron overload, alcohol abuse or hepatitis C virus infection. Stopping tamoxifen is followed by gradual improvement in symptoms, decrease in porphyrin excretion and improvement in liver enzymes.
Likelihood score: B (highly likely but rare cause of clinically apparent liver injury).
An oral dose of 20mg reaches a Cmax of 40ng/mL with a Tmax of 5 hours. The metabolite N-desmethyltamoxifen reaches a Cmax of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a Css of 120ng/mL and a Css of 336ng/mL.
Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% in the feces.
来源:DrugBank
吸收、分配和排泄
分布容积
他莫昔芬的分布体积大约是50-60升/千克。
The volume of distribution of tamoxifen is approximately 50-60L/kg.
来源:DrugBank
吸收、分配和排泄
清除
在六名绝经后妇女的研究中，他莫昔芬的清除率为189毫升/分钟。
The clearance of tamoxifen was 189mL/min in a study of six postmenopausal women.
Tamoxifen appears to be absorbed slowly following oral administration, with peak serum concentrations generally occurring about 3-6 hours after a single dose. The extent of absorption in humans has not been adequately determined, but limited data from animal studies suggest that the drug is well absorbed. Data from animal studies also suggest that tamoxifen and/or its metabolites undergo extensive enterohepatic circulation.
[EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
申请人：UNIV TEXAS
公开号：WO2017007634A1
公开（公告）日：2017-01-12
The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.
[EN] TARGETED DELIVERY AND PRODRUG DESIGNS FOR PLATINUM-ACRIDINE ANTI-CANCER COMPOUNDS AND METHODS THEREOF<br/>[FR] ADMINISTRATION CIBLÉE ET CONCEPTIONS DE PROMÉDICAMENTS POUR COMPOSÉS ANTICANCÉREUX À BASE DE PLATINE ET D'ACRIDINE ET MÉTHODES ASSOCIÉES
申请人：WAKE FOREST SCHOOL OF MEDICINE
公开号：WO2013033430A1
公开（公告）日：2013-03-07
Acridine containing cispiaiin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective eisp!aiin compounds to the nucleus in cancer ceils is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C i^aikylene-phenyl-NH-C(0)-R.15, folic acid, av03 iniegriii RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazol.es, oxazoies, erlotinib, and/or mixtures thereof; wherein R]§ is a peptide.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] COMPOUNDS FOR USE AS PROTON CHANNELS AND METHODS THEREOF<br/>[FR] COMPOSÉS DESTINÉS À ÊTRE UTILISÉS EN TANT QUE CANAUX DE PROTONS ET PROCÉDÉS ASSOCIÉS
申请人：AGENCY SCIENCE TECH & RES
公开号：WO2020159441A1
公开（公告）日：2020-08-06
The present disclosure relates generally to compounds or a salt, solvate, stereoisomer and prodrug thereof for forming synthetic membrane channels. The present disclosure also relates to methods of synthesizing the compounds, methods of forming the synthetic membrane channels and methods of use thereof. In particular, the synthetic membrane channels are synthetic proton channels in a lipid membrane.
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.
