Interaction potential of the endothelin-A receptor antagonist atrasentan with drug transporters and drug-metabolising enzymes assessed in vitro

Purpose: Atrasentan is a highly potent and selective Endothelin Receptor A (ET(A)) antagonist under development for the treatment of prostate Cancer. Only little data exist on its interaction with drug-metabolising Enzymes and drug transporters possibly influencing its safety and effectiveness. Our study evaluated whether atrasentan can induce the expression of relevant human drug transporters and Cytochrome P450 isozymes (CYPs), whether it retains its efficiency in multidrug resistant cell lines, and whether it inhibits P-glycoprotein (P-gp) and breast Cancer resistance protein (BCRP).

Methods: Induction of transporters and Enzymes was quantified at the mRNA level by real-time RT-PCR in LS180 cells and for P-gp also at the protein level by Western blot. P-gp inhibition was evaluated by calcein assay in P388/dx and L-MDR1 cells and BCRP inhibition in MDCKII-BCRP cells by pheophorbide A efflux. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC-transporters.

Results: Atrasentan profoundly induced several CYPs and drug transporters (e.g. 12-fold induction of CYP3A4 at 50 μM). It was a moderate P-gp inhibitor (IC(50) in P388/dx cells = 15.1 ± 1.6 μM) and a weak BCRP Inhibitor (IC(50) in MDCKII-BCRP cells = 59.8 ± 11 μM). BCRP or P-gp overexpressing cells were slightly more resistant towards antiproliferative effects of atrasentan.

Conclusions: Our data provide a comprehensive analysis of the induction profile of atrasentan and its interaction with P-gp and BCRP. The profound induction effects stress the need for thorough assessment of its interaction potential in vivo.