Temsirolimus

Các tên gọi khác (3) :

42-[3-Hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin
CCI 779
Torisel

Thuốc Gốc

Small Molecule

CAS: 162635-04-3

ATC: L01XE09

ĐG : Ben Venue Laboratories Inc. , http://www.benvenue.com

CTHH: C₅₆H₈₇NO₁₆

PTK: 1030.2871

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.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₅₆H₈₇NO₁₆

Phân tử khối

1030.2871

Monoisotopic mass

1029.602485741

InChI

InChI=1S/C56H87NO16/c1-33-17-13-12-14-18-34(2)45(68-9)29-41-22-20-39(7)56(67,73-41)51(63)52(64)57-24-16-15-19-42(57)53(65)71-46(30-43(60)35(3)26-38(6)49(62)50(70-11)48(61)37(5)25-33)36(4)27-40-21-23-44(47(28-40)69-10)72-54(66)55(8,31-58)32-59/h12-14,17-18,26,33,35-37,39-42,44-47,49-50,58-59,62,67H,15-16,19-25,27-32H2,1-11H3/b14-12+,17-13+,34-18+,38-26+/t33-,35-,36-,37-,39-,40+,41+,42+,44-,45+,46+,47-,49-,50+,56-/m1/s1

InChI Key

InChIKey=CBPNZQVSJQDFBE-FUXHJELOSA-N

IUPAC Name

(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

Traditional IUPAC Name

SMILES

OCC(C)(CO)C(=O)O[C@@H]1CC[C@@H](C[C@@H](C)[C@]2([H])CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@@H](OC)C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC

Độ hòa tan

2.35e-03 g/l

logP

7.13

logS

-5.6

pKa (strongest acidic)

9.96

pKa (Strongest Basic)

-2.9

PSA

241.96 Å²

Refractivity

277.07 m³·mol^-1

Polarizability

112.71 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

Cơ Chế Tác Dụng : 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. 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.

Dược Động Học :

▧ 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.
▧ 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%)

Độc Tính : 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.

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

Tương Tác Thuốc :

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.
Rifampicin 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.

Liều Lượng & Cách Dùng : Solution - Intravenous - 25 mg/mL

Dữ Kiện Thương Mại

Giá thị trường

Biệt dược thương mại : Torisel 25 mg kit

Giá bán buôn : USD >1467.89

Đơn vị tính : ml

Nhà Sản Xuất

Công ty :

Sản phẩm biệt dược : Torisel

Đóng gói

Công ty : Ben Venue Laboratories Inc.

Website : http://www.benvenue.com
Công ty : Chunghwa Chemical Synthesis and Biotech Co. Ltd.

Website : http://www.ccsb.com.tw
Công ty : Pierre Fabre

Website : http://www.pierre-fabre.com
Công ty : Wyeth Pharmaceuticals

Website : http://www.wyeth.com

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06287

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=23724530

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=99443243

KEGG Compound

http://www.genome.jp/dbget-bin/www_bget?cpd:C15182

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D06068

ChemSpider

http://www.chemspider.com/Chemical-Structure.21468899.html

PharmGKB

http://www.pharmgkb.org/drug/PA164746890

Wikipedia

http://en.wikipedia.org/wiki/Temsirolimus

RxList

http://www.rxlist.com/cgi/generic/torisel.htm

Drugs.com

http://www.drugs.com/cdi/temsirolimus.html

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