Pgp/MDR1 Specific Inhibitor-PSC 883 (valspador/Amray)

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PSC 833, a non-immunosuppressive cyclosporine D analog, is a 2nd generation ABCB1/P-gp/MDR1 specific reversal agent. We have confirmed that PSC 833 is a specific P-gp inhibitor by measuring the inhibitory potential of PSC 833 on a group of apically localized efflux transporters (Fig. 1). In the vesicular transport assay, the IC50 for P-gp mediated N-methyl-quinidine (NMQ) transport inhibition was ~10nM, about 2 logs below the IC50 for ABCG2/BCRP/MXR mediated estrone-3-sulfate (E3S) inhibition and more than 2 logs below the IC50 for inhibition of dehydroepiandrosterone-sulfate (DHEAS) transport by ABCC4/MRP4. Dose-dependent inhibition of estradiol-17β-glucuronide (E217βG) transport mediated by MRP2 was not clearly detected.

In addition, PSC 833 was found to be very effective in the monolayer efflux assays. In MDCKII-MDR1 cells the digoxin efflux ratio was reduced from 11.2 to 1.22 (Fig.2).

The fact that a broad set of preclinical and clinical data is available for this compound (reviewed in Tai 2000 Curr Opin Mol Ther 2:459) makes PSC 833 especially valuable for in vitro and in vivo ADME studies. 

Figure 1. Specificity of PSC 833 to inhibit major apical efflux transporters in the vesicular transport assay.  NMQ, E3S, DHEA and E217ßG transport was measured individually in the presence of various concentrations of PSC 833 using radioactive probe substrates. Relative trasport (vesicular uptake) values were calculated. 

Figure 2. Bidirectional permeability of labelled digoxin in MDCKII-MDR1 cells in the presence and absence of PSC 833. Digoxin (10 µM) apparent permeability (Papp) was calculated.

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