Tìm theo
Pazopanib
Các tên gọi khác (3) :
  • GW 78603
  • GW786034
  • Pazopanibum
Thuốc Gốc
Small Molecule
CAS: 444731-52-6
ATC: L01XE11
CTHH: C21H23N7O2S
PTK: 437.518
Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C21H23N7O2S
Phân tử khối
437.518
Monoisotopic mass
437.163393705
InChI
InChI=1S/C21H23N7O2S/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25)
InChI Key
InChIKey=CUIHSIWYWATEQL-UHFFFAOYSA-N
IUPAC Name
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide
Traditional IUPAC Name
pazopanib
SMILES
CN(C1=CC2=NN(C)C(C)=C2C=C1)C1=CC=NC(NC2=CC=C(C)C(=C2)S(N)(=O)=O)=N1
Độ hòa tan
4.33e-02 g/l
logP
3.55
logS
-4
pKa (strongest acidic)
10.41
pKa (Strongest Basic)
5.07
PSA
119.03 Å2
Refractivity
132.18 m3·mol-1
Polarizability
45.41 Å3
Rotatable Bond Count
5
H Bond Acceptor Count
7
H Bond Donor Count
2
Physiological Charge
0
Number of Rings
4
Bioavailability
1
Rule of Five
true
Dược Lực Học : Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01 - 0.084 μmol/L). A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.
Cơ Chế Tác Dụng : Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009. Pazopanib is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth.
Dược Động Học :
▧ Absorption :
Absorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;
▧ Volume of Distribution :
Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4)
▧ Protein binding :
>99% protein bound, independent of concentrations over a range of 10-100 μg/mL.
▧ Metabolism :
Metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8. Metabolites are less active than pazopanib (10 to 20-fold less active). Three of its metabolites can be observed in the systemic and account for <10% of plasma radioactivity.
▧ Route of Elimination :
Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.
▧ Half Life :
35 hours. Oral absorption is not the rate limiting step of elimination from the plasma.
▧ Clearance :
CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism.
Chỉ Định : Treatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated with chemotherapy)
Tương Tác Thuốc :
  • Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
  • Carbamazepine Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Cimetidine Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Clarithromycin Clarithromycin is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib.
  • Conivaptan CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pazopanib. Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib dose to 400 mg. Further dose reductions may also be required.
  • Erythromycin Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Etravirine Pazopanib, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
  • Ifosfamide Ifosfamide decreases plasma levels of pazopanib.
  • Irinotecan Irinotecan is an uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) substrate and serum concentrations may increase if administered concurrently with pazopanib, an UGT1A1 inhibitor.
  • Itraconazole Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Ivacaftor Inhibits p-glycoprotein and affects heptatic metabolism via CYP3A4 therefore increases levels of pazopanib. Consider alternate therapy.
  • Ketoconazole Ketoconazole is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib by 120% in healthy subjects.
  • Lapatinib Lapatinib is a weak inhibitor of CYP3A4, BCRP, and p-glycoprotein and may increase exposure of pazopanib. AUC and Cmax increase by 50-60%.
  • Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
  • Nefazodone Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Ondansetron Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
  • Paclitaxel Pazopanib increases exposure of paclitaxel
  • Rifabutin Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Rifampicin Concomitant therapy with a CYP3A4 inducer may decrease exposure of pazopanib.
  • Ritonavir Ritonavir is a strong inhibitor of CYP3A4 thus increasing exposure of pazopanib.
  • Saquinavir Affects CYP3A4 metabolism therefore will decrease levels or effect of pazopanib. Consider alternate therapy.
  • Simvastatin Elevated liver enzyme levels may be observed with concomitant therapy with pazopanib. Monitor closely for adverse effects.
  • Toremifene Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
  • Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
  • Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Liều Lượng & Cách Dùng : Tablet - Oral - 200 mg
Dữ Kiện Thương Mại
Nhà Sản Xuất
Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB06589
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D05380
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0173-0804-09
Wikipedia
http://en.wikipedia.org/wiki/Pazopanib
RxList
http://www.rxlist.com/votrient-drug.htm
Drugs.com
http://www.drugs.com/cdi/pazopanib.html
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