Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 can deacetylate tamsulosin to the M-1 metabolite or perform oxidative deamination to the AM-1 metabolite. CYP2D6 can hydroxylate tamsulosin to the M-3 metabolite or demethylate tamsulosin to the M-4 metabolite. Finally, an unknown enzyme can hydroxylate tamsulosin at a different position to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated or the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion.
来源:DrugBank
代谢
广泛被肝脏中的细胞色素P450酶（具体同工酶未确定）代谢。代谢物在排泄前会进一步发生结合反应。
Extensively metabolized by CYP enzymes (specific isoenzyme[s] not identified) in the liver. Metabolites undergo further conjugation prior to excretion.
There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increased exposure to tamsulosin. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
... After a single oral administration of 14C-tamsulosin at a dose of 0.2 mg /to/ four healthy male subjects... unchanged tamsulosin (TMS) and 11 metabolites in 0-24-hr urine samples were quantified. TMS accounted for 8.7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15.7 and 7.5% of the dose respectively.
The metabolism of tamsulosin hydrochloride (TMS), a potent alpha 1-adrenoceptor blocking agent, was studied after a single oral administration to rat and dog. Eleven metabolites (1, 2, 3, 4 and their glucuronides, sulphates of 1 and 3, and A-1) were identified from the urine and bile of rat and dog administered TMS. Unchanged drug and metabolites in urine and bile were quantified in rat and dog dosed with 14C-TMS(1 mg/kg). In rat the main metabolic routes were de-ethylation of the o-ethoxyphenoxy moiety, demethylation of the methoxybenzenesulphonamide moiety, and conjugation of the resultant metabolites by glucuronic acid and sulphuric acid. In dog the main pathways were de-ethylation of the ethoxyphenoxy moiety, conjugation of the de-ethylated product by sulphuric acid, and oxidative deamination of the side chain. The organ responsible for the metabolism of TMS in rat was estimated using 9000g supernatants of liver, kidney, small and large intestine homogenate and plasma. The drug was rapidly metabolized in liver but hardly metabolized in the other organs or plasma.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
坦索罗辛与血清转氨酶升高的低发生率有关（
Tamsulosin has been associated with a low rate of serum aminotransferase elevations (
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Oral tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL\*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%.
97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin.
In patients with moderate hepatic impairment, protein binding is altered, resulting in changes in overall plasma concentrations; however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.
[EN] SYNTHESIS OF OPTICALLY PURE (R)-5-(2-AMINOPROPYL)-2-METHOXYBENZENESULPHONAMIDE [FR] SYNTHESE DE (R)-5-(2-AMINOPROPYL)-2-METHOXYBENZENOSULFONAMIDE OPTIQUEMENT PUR
Process for the resolution of racemic (R,S) -5-(2-(2-(2- ethoxyphenoxy) ethylamino)Propyl)-2-methoxybenzene sulfonamide (tamsulosin), its novel R and S isomers and their salts and processes for their preparation
[EN] PYRIMIDINE JAK INHIBITORS FOR THE TREATMENT OF SKIN DISEASES<br/>[FR] INHIBITEURS DE JAK À BASE DE PYRIMIDINE POUR LE TRAITEMENT DE MALADIES DE LA PEAU
申请人：THERAVANCE BIOPHARMA R&D IP LLC
公开号：WO2020219640A1
公开（公告）日：2020-10-29
The invention provides compounds of formula (I): or pharmaceutically-acceptable salts thereof, that are inhibitors of Janus kinases. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune skin diseases.
Substituted 1-benzoyl-3-cyano-pyrrolo [1,2-a] quinolines and analogs as activators of caspases and inducers of apoptosis
申请人：Cai Xiong Sui
公开号：US20050014759A1
公开（公告）日：2005-01-20
The present invention is directed to substituted 1-benzoyl-3-cyano-pyrrolo[1,2-a]quinolines and analogs thereof, represented by the general Formula I:
wherein R
1
—R
8
, L, Q, dash line and Ar are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.
[EN] FUSED QUINOLINE DERIVATIVE AND USE THEREOF<br/>[FR] DÉRIVÉ DE QUINOLINE FUSIONNÉE ET UTILISATION DE CELUI-CI
申请人：TAKEDA PHARMACEUTICAL
公开号：WO2005105802A1
公开（公告）日：2005-11-10
The present invention aims at provision of a quinoline derivative having a neurokinin 2 (NK2) receptor antagonistic action and relates to a compound represented by the formula (I) wherein Rl is a hydrogen atom and the like; R2 is a hydrogen atom, a hydrocarbon group optionally having substituent(s) and the like; R3 is unsubstituted (i.e., absence), a hydrogen atom and the like; R4 and R5 are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s), and the like; R6 is (cyclic group optionally having substituent(s)) -carbonyl, and the like; R7, R8, R9 and R10 are the same or different and each is a hydrogen atom, halogen and the like; or R7 and R8, R8 and R9, and R9 and R10 may form a ring together with the adjacent carbon atoms; n is an integer of 1 to 5; --- represents unsubstituted (i.e., absence) or a single bond; and --- represents a single bond or a double bond, or a salt thereof, and the like.
[EN] AMIDOIMIDAZOPYRIDAZINES AS MKNK-1 KINASE INHIBITORS<br/>[FR] AMIDOIMIDAZOPYRIDAZINES À TITRE D'INHIBITEURS DE KINASES MKNK-1
申请人：BAYER PHARMA AG
公开号：WO2014118135A1
公开（公告）日：2014-08-07
The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
