生物活性

• 靶点

  Hedgehog IC50:3nM

  P-gp IC50:3.0μM

• 描述The Hedgehog (HH) signaling pathway is closely linked to developmental processes, organ patterning, tissue and stem cell maintenance, cell differentiation processes, cell proliferation, regenerative responses after injury and cancer formation^[6]. Vismodegib (GDC-0449) is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, with IC50 values of 1.4 and 3.0 µM, respectively. Additionally, vismodegib can also mildly inhibit ABCC1/MRP1 ^[7]. In vitro, vismodegib can inhibited cell viability and induce apoptosis in pancreatic cancer cell lines (AsPC-1, PANC-1 and MIA PaCa-2) at 72 hours with IC50 less than 10 μM. Vismodegib-induced apoptosis in cancer cell lines showed increased Fas expression and decreased expression of PDGFRa^[8]. After exposed to 50 μM vismodegib for 2 days, survival fraction of HCC and H1339 cells reduced to 60% and 50%, respectively. Ca²⁺ imaging showed that vismodegib increased [Ca²⁺](cyto) and reduced endoplasmatic [Ca²⁺](ER)^[1]. When the mouse model of nonalcoholic steatohepatitis was treated with vismodegib (25 mg/kg), TRAIL-mediated liver injury was significantly suppressed and serum ALT and hepatic TUNEL-positive cells were reduced^[9].

• 动物研究
  剂量	Rat: 10 mg/kg - 300 mg/kg[3] (p.o.) Nude Mice: 5 mg/kg - 100 mg/kg[4] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[5] Rats[5] Dogs[5] Monkeys[5] Dose 1 mg/kg (i.v.) 5 mg/kg (p.o.) 1 mg/kg (i.v.) 5 mg/kg (p.o.) 1 mg/kg (i.v.) 2 mg/kg (p.o.) 1 mg/kg (i.v.) 5 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. MRT 1.22 h (i.v.) 1.89 ± 0.508 h (i.v.) 62.3 ± 30.0 h (i.v.) 0.855 ± 0.101 h (i.v.) F 19.2% (p.o.) 52.9% (p.o.) 32.9% (p.o.) 13.4 ± 2.07% (p.o.) T1/2 0.976 h (i.v.) 1.32 ± 0.258 h (i.v.) 41.8 ± 19.8 h (i.v.) 0.581 ± 0.0922 h (i.v.) Tmax 1.00 h (p.o.) 0.667 ± 0.289 h (p.o.) 9.33 ± 12.7 h (p.o.) 2.00 ± 0.00 h (p.o.) AUCinf 725 ng·h/ml (i.v.) 696 ng·h/ml (p.o.) 3980 ± 1540 ng·h/ml (i.v.) 10500 ± 3150 ng·h/ml (p.o.) 60000 ± 26800 ng·h/ml (i.v.) 39400 ± 5800 ng·h/ml (p.o.) 957 ± 387 ng·h/ml (i.v.) 256 ± 112 ng·h/ml (p.o.) CL 23.0 ml·min/kg (i.v.) 4.65 ± 1.81 ml·min/kg (i.v.) 0.338 ± 0.203 ml·min/kg (i.v.) 19.3 ± 6.93 ml·min/kg (i.v.) Cmax 311 ng/ml (p.o.) 2760 ± 1020 ng/ml (p.o.) 591 ± 97.7 ng/ml (p.o.) 162 ± 121 ng/ml (p.o.) Vss 1.68 L/kg (i.v.) 0.490 ± 0.0653 L/kg (i.v.) 1.03 ± 0.119 L/kg (i.v.) 0.984 ± 0.342 L/kg (i.v.)