CP-100356 hydrochloride is an orally active, low micromolar dual inhibitor of MDR1 (P-gp) and BCRP, a nucleotide-derived substrate analogue that inhibits MDR1-mediated Calcein-AM and BCRP-mediated Prazosin transporters. Additionally, CP-100356 inhibits OATP1B1 and induces stomatal opening in the dark.

MDR1:0.5 µM, BCRP:1.5 µM (in MDCKII cells)

In human MDR1-transfected MDCKII cells, CP-100356 hydrochloride inhibited acetoxymethyl calcein (calcein-AM) uptake (IC50 approximately 0.5 +/- 0.07 microM) and digoxin transport (IC50 approximately 1.2 +/- 0.1 microM). Inhibition of prazosin transport (IC50 approximately 1.5 +/- 0.3 microM) in human BCRP-transfected MDCKII cells by CP-100356 hydrochloride confirmed the dual MDR1/BCRP inhibitory properties[1].

In vivo inhibitory effects of CP-100356 hydrochloride in rats were examined after coadministration with MDR1 substrate fexofenadine and dual MDR1/BCRP substrate prazosin. Coadministration with increasing doses of CP-100356 hydrochloride resulted in dramatic increases in systemic exposure of fexofenadine (36- and 80-fold increase in C(max) and AUC at a CP-100356 hydrochloride dose of 24 mg/kg). Significant differences in prazosin pharmacokinetics were also discernible in CP-100356 hydrochloride-pretreated rats as reflected from a 2.6-fold increase in AUC.[1].