title: Interactions of bilastine, a new oral H₁ antihistamine, with human transporter systems.
abstract: Membrane transporters play a significant role in facilitating transmembrane drug movement. For new pharmacological agents, it is important to evaluate potential interactions (e.g., substrate specificity and/or inhibition) with human transporters that may affect their pharmacokinetics, efficacy, or toxicity. Bilastine is a new nonsedating H₁ antihistamine indicated for the treatment of allergic rhinoconjunctivitis and urticaria. The in vitro inhibitory effects of bilastine were assessed on 12 human transporters: four efflux [multidrug resistance protein 1 (MDR1) or P-glycoprotein, breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), and bile salt export pump) and eight uptake transporters (sodium taurocholate cotransporting polypeptide, organic cation transporter (OCT)1, organic anion transporter (OAT)1, OAT3, OCT2, OATP2B1, OATP1B1, and OATP1B3). Only mild inhibition was found for MDR1-, OCT1-, and OATP2B1-mediated transport of probe substrates at the highest bilastine concentration assayed (300 μM; half-maximal inhibitory concentration: ≥300 μM). Bilastine transport by MDR1, BCRP, OAT1, OAT3, and OCT2 was also investigated in vitro. Only MDR1 active transport of bilastine was relevant, whereas it did not appear to be a substrate of OCT2, OAT1, or OAT3, nor was it transported substantially by BCRP. Drug-drug interactions resulting from bilastine inhibition of drug transporters that would be generally regarded as clinically relevant are unlikely. Additionally, bilastine did not appear to be a substrate of human BCRP, OAT1, OAT3, or OCT2 and thus is not a potential victim of inhibitors of these transporters. On the other hand, based on in vitro evaluation, clinically relevant interactions with MDR1 inhibitors are anticipated.
authors.affiliation: Faes Farma, SA, Leioa, Spain. mlucero@faes.es
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Lucero
authors.forename: Ana
authors.initials: A
authors.lastname: Gonzalo
authors.forename: Alvaro
authors.initials: A
authors.lastname: Ganza
authors.forename: Nerea
authors.initials: N
authors.lastname: Leal
authors.forename: Itziar
authors.initials: I
authors.lastname: Soengas
authors.forename: Eniko
authors.initials: E
authors.lastname: Ioja
authors.forename: Szilvia
authors.initials: S
authors.lastname: Gedey
authors.forename: Mirza
authors.initials: M
authors.lastname: Jahic
authors.forename: Dallas
authors.initials: D
authors.lastname: Bednarczyk
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D016466:CHO Cells; D018938:Caco-2 Cells; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D010880:Piperidines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018411:Spodoptera
chemical_list: D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D039563:Histamine H1 Antagonists, Non-Sedating; D049990:Membrane Transport Modulators; D027361:Organic Anion Transporters; D010880:Piperidines; D020033:Protein Isoforms; D011994:Recombinant Proteins; C445659:bilastine