GDC-0449 (Vismodegib) is a potent and specific hedgehog (Hh) pathway, also inhibits ABCG2, Pgp and MRP1-important ABC transporters associated with MDR. The IC50 values of GDC-0449 for inhibition of ABCG2 and Pgp were 1.4 and 3.0μM, respectively. GDC-0449 (Vismodegib) has been used to treat medulloblastoma in animal models and has recently entered clinical trials for a variety of solid tumors.
Nature. 2020 Dec;588(7839):664-669.
Creation of bladder assembloids mimicking tissue regeneration and cancer
GDC-0449 (Vismodegib) purchased from AbMole
 |
Source | Pharma Res (2017). Figure 7. GDC-0449 |
| Method | i.v. | |
| Cell Lines | mice | |
| Concentrations | 10 mg/kg | |
| Incubation Time | 15, 30, 60, 240, 720 and 1440 min | |
| Results | For the 20% M6P-conjugated micelles, GDC-0449 concentration increased by 30.60% compared to non targeted micelles in normal mice and by 50.36% in fibrotic mice liver |
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Source | Pharma Res (2017). Figure 6. GDC-0449 |
| Method | i.v. | |
| Cell Lines | mice | |
| Concentrations | 10 mg/kg | |
| Incubation Time | 15, 30, 60, 240, 720 and 1440 min | |
| Results | Liver fibrosis results changes in the subendothelial space of Disse and sinusoid due to scar formation, which may affect the hepatic uptake of GDC-0449. The hepatic uptake of GDC-0449 after systemic administration of drug loaded micelles decreased from ~40% to ~30% |
| Cell Experiment | |
|---|---|
| Cell lines | OM9;22 cell line |
| Preparation method | Cell proliferation assay The cells were seeded in 24- or 96-well plates at a density of 2 *105 mL -1 in the presence or absence of S9 feeder cells. The cells were treated with the inhibitor drugs at the indicated concentrations: dasatinib, 1–100nM; and GDC-0449, 100nM to 10 mM. Viable cells were counted by trypan blue exclusion or fluorescence-activated cell sorting. |
| Concentrations | 100nM to 10 µM |
| Incubation time | 48h |
| Animal Experiment | |
|---|---|
| Animal models | Medulloblastoma allografts model in mice |
| Formulation | 0.5% methyl-cellulose, 0.2% tween-80 (MCT) |
| Dosages | 0.3 to 75 mg/kg daily |
| Administration | oral gavage |
| Molecular Weight | 421.3 |
| Formula | C19H14Cl2N2O3S |
| CAS Number | 879085-55-9 |
| Solubility (25°C) | DMSO 50 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[3] Keating GM. Drugs. Vismodegib: in locally advanced or metastatic Basal cell carcinoma.
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