药品详细

Temsirolimus(西罗莫司)

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

西罗莫司

英文名

Temsirolimus

分子式

C₅₆H₈₇NO₁₆

化学名

(1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

分子量

Average: 1030.2871
Monoisotopic: 1029.602485741

CAS号

162635-04-3

ATC分类

L01X 其它抗肿瘤药

药物类型

small molecule

阶段

approved

商品名

Torisel;

同义名

CCI-779;temsirolimus;

基本介绍

Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the FDA in late May 2007, and was also approved by the European Medicines Agency (EMEA) on November 2007. It is a derivative of sirolimus and is sold as Torisel.

生产厂家

Wyeth pharmaceuticals inc

封装厂家

参考

Synthesis Reference	Not Available
General Reference	Wyeth Pharmaceuticals Inc. Torisel® (temsirolimus) injection prescribing information. Philadelphia, PA: 2010 Sep. Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L: Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome p450-inducing medications. J Clin Pharmacol. 2007 Nov;47(11):1430-9. Epub 2007 Oct 3. Pubmed

剂型

规格

化合物类型

Type	small molecule

Classes

Carbonyl Compounds
Pyrans
Amino Acids
Lactams
Piperidines

Substructures

Carbonyl Compounds
Carboxylic Acids and Derivatives
Hydroxy Compounds
Alkanes and Alkenes
Pyrans
Acetates
Lactones
Amino Ketones
Acetals and Derivatives
Ethers
Aliphatic and Aryl Amines
Alcohols and Polyols
Heterocyclic compounds
Carboxamides and Derivatives
Amino Acids
Lactams
Piperidines
Ketones

适应症

;IMMUNOSUPPRESSIVE 免疫抑制;

药理

Indication

For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma.

Pharmacodynamics

Not Available

Mechanism of action

Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.

Absorption

Infused intravenous over 30 - 60 minutes. C_max is typically observed at the end of infusion

Volume of distribution

172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements

Protein binding

87% bound to plasma proteins in vitro at a concentration of 100 ng/ml

Metabolism

Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate	Enzymes	Product
Temsirolimus		Sirolimus	Details

Route of elimination

Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.

Half life

Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.

Clearance

16.2 L/h (22%)

Toxicity

Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg.

Affected organisms

Humans and other mammals

Pathways

Not Available

理化性质

Properties

State

solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
water solubility	2.35e-03 g/l	ALOGPS
logP	4.39	ALOGPS
logP	7.13	ChemAxon
logS	-5.6	ALOGPS
pKa (strongest acidic)	9.96	ChemAxon
pKa (strongest basic)	-2.9	ChemAxon
physiological charge	0	ChemAxon
hydrogen acceptor count	14	ChemAxon
hydrogen donor count	4	ChemAxon
polar surface area	241.96	ChemAxon
rotatable bond count	11	ChemAxon
refractivity	277.07	ChemAxon
polarizability	112.71	ChemAxon

药物相互作用

Drug	Interaction
Aminoglutethimide	Aminoglutethimide may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Amprenavir	Amprenavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Atazanavir	Atazanavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Bosentan	Bosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Carbamazepine	Carbamazepine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Clarithromycin	Clarithromycin may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Conivaptan	Conivaptan may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Darunavir	Darunavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Delavirdine	Delavirdine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Dexamethasone	Dexamethasone may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Efavirenz	Efavirenz may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Fluorouracil	Co-administration of Temsirolimus and Fluorouracil may result in serious adverse drug reactions.
Fosamprenavir	Fosamprenavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Fosphenytoin	Fosphenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Gemcitabine	Co-administration of Temsirolimus and Gemcitabine may result in serious adverse drug reactions.
Imatinib	Imatinib may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Indinavir	Indinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Isoniazid	Isoniazid may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Itraconazole	Itraconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Ketoconazole	Ketoconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Lopinavir	Lopinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Miconazole	Miconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Nafcillin	Nafcillin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Natalizumab	Temsirolimus may increase the toxicity of Natalizumab. Concomitant therapy should be avoided.
Nefazodone	Nefazodone may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Nelfinavir	Nelfinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Nevirapine	Nevirapine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Nicardipine	Nicardipine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Oxcarbazepine	Oxcarbamazepine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Pentobarbital	Pentobarbital may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Phenobarbital	Phenobarbital may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Phenytoin	Phenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Posaconazole	Posaconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Primidone	Primidone may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Quinidine	Quinidine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Rifabutin	Rifabutin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Rifampin	Rifampin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Rifapentine	Rifapentine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Rilonacept	results in increased immunosuppressive effects; increases the risk of infection.
Ritonavir	Ritonavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Saquinavir	Saquinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
St. John's Wort	St. John's Wort may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.
Sunitinib	Co-administration of Temsirolimus and Sunitinib may result in serious adverse drug reactions.
Tacrolimus	Temsirolimus may decrease the blood concentration of Tacrolimus. Concomitant therapy may increase the adverse/toxic effects of both agents. Concomitant therapy should be avoided.
Telithromycin	Telithromycin may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Tipranavir	Tipranavir may affect the efficacy/toxicity of Temsirolimus.
Trandolapril	Increased risk of angioedema. Monitor for signs and symptoms of facial and systemic edema and/or erythema.
Trastuzumab	Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Voriconazole	Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of temsirolimus and its active metabolite, sirolimus, by decreasing their metabolism. Concomitant therapy should be avoided.

食物相互作用

Not Available

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