title: Evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers.
abstract: OBJECTIVE
  The objective of the present study was to evaluate drug efflux transporter interactions of darifenacin and examine the impact of such transporter interactions on darifenacin permeability in an in vitro model of the blood-brain barrier (BBB) and blood-ocular barrier (BOB).
  
  
  METHODS
  Cell membranes expressing human P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) were examined for ATPase activity following darifenacin exposure (0-10  µM). Primary cultured bovine brain microvessel endothelial cells (BBMEC) and P-gp transfected Manin-Darby canine kidney epithelial cells (MDCKMDR1) were used to examine darifenacin permeability and drug efflux transporter responses.
  
  
  RESULTS
  Concentration-dependent increases in ATPase activity was observed in P-gp membranes following darifenacin exposure. Both MRP and BCRP membrane preparations were unresponsive to darifenacin. Studies in both BBMEC and MDCKMDR1 monolayers confirmed a P-gp interaction for darifenacin and significantly greater efflux (basolateral to apical) permeability for darifenacin that was reduced by the P-gp inhibitor, elacridar.
  
  
  CONCLUSIONS
  Darifenacin is a substrate for the P-gp drug efflux transporter present in both BBB and BOB. The P-gp drug efflux transporter liabilities of darifenacin may limit its penetration into brain and ocular tissue thereby reducing side effect potential.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. miller5@cc.umanitoba.ca
authors.forename: Donald W
authors.initials: DW
authors.lastname: Miller
authors.forename: Martha
authors.initials: M
authors.lastname: Hinton
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D018916:Blood-Aqueous Barrier / Q000187:drug effects / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000378:metabolism* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D010539:Permeability; D011759:Pyrrolidines / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D001572:Benzofurans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018727:Muscarinic Antagonists; D009363:Neoplasm Proteins; D011759:Pyrrolidines; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C101207:darifenacin