title: Interaction potential of the endothelin-A receptor antagonist atrasentan with drug transporters and drug-metabolising enzymes assessed in vitro.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. johanna.weiss@med.uni-heidelberg.de
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000077868:Atrasentan; D002460:Cell Line; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004285:Dogs; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D065130:Endothelin A Receptor Antagonists; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007941:Leukemia P388 / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D009363:Neoplasm Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D000077868:Atrasentan