In vitro: Valspodar (PSC 833) has no cytotoxicity effects at up to the concentration of 0.75 μg/mL. Valspodar (0.25, 0.5 and 0.75 μg/mL) and DOX-L are added to the DOX resistant cells, and cell kill efficacy of MDR cell type increases significantly when valspodar is administered alongside DOX-L. Valspodar (0.5 and 0.75 μg/mL), in combination with all concentrations of DOX, are most toxic and kill more than 70% of the resistant cells. Pretreatment with PSC833 decreases the IC50 value of mitoxantrone in MDA-MB-435mdr cells to 0.4±0.02 μM in MDR cells and almost completely reverses the resistance of MDR cells to mitoxantrone.
In vivo: valspodar (10 mg/kg, o.p.) exhibits minimal blood-cell partitioning as reflected in its low mean blood-to-plasma ratio of approximately 0.52. Valspodar displays properties of slow clearance and a large volume of distribution. Valspodar shows properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A. Preadministration of PSC833 to mice increases mitoxantrone fluorescent intensity in MDR tumor to 94% of that in the wild-type tumors.
|Cell lines||T47D/TAMR-6 cells|
|Preparation method||After 48 hours incubation, fresh medium containing serial concentration of various drug formulations, including free DOX, DOX-L, mixture of DOX-L and free Valspodar (PSC 833), mixture of DOX-L and PSC-L and DOX/PSC-L are added. The plates are then incubated for an additional 48 hours before washing with normal saline followed by adding MTT solution (0.5 mg/mL) to each well, and incubated for 4 h at 37°C.|
|Incubation time||48 h|
|Animal models||Male Sprague–Dawley rats|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||12 mg/mL in DMSO|
Development of a polymeric micellar formulation for valspodar and assessment of its pharmacokinetics in rat.
Binkhathlan Z, et al. Eur J Pharm Biopharm. 2010 Jun;75(2):90-5.. PMID: 20332028.
Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat.
Binkhathlan Z, et al. Xenobiotica. 2010 Jan;40(1):55-61. PMID: 19903013.
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