Interactions of bilastine, a new oral H₁ antihistamine, with human transporter systems

Drug Chem Toxicol. 2012 Jun:35 Suppl 1:8-17. doi: 10.3109/01480545.2012.682653.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Benzimidazoles / adverse effects
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Biological Transport
  • CHO Cells
  • Caco-2 Cells
  • Cell Line
  • Cell-Free System / metabolism
  • Cricetinae
  • Cricetulus
  • Dogs
  • Drug Evaluation, Preclinical
  • Histamine H1 Antagonists, Non-Sedating / adverse effects
  • Histamine H1 Antagonists, Non-Sedating / metabolism
  • Histamine H1 Antagonists, Non-Sedating / pharmacology*
  • Humans
  • Membrane Transport Modulators / adverse effects
  • Membrane Transport Modulators / metabolism
  • Membrane Transport Modulators / pharmacology*
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism
  • Osmolar Concentration
  • Piperidines / adverse effects
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Spodoptera

Substances

  • ATP-Binding Cassette Transporters
  • Benzimidazoles
  • Histamine H1 Antagonists, Non-Sedating
  • Membrane Transport Modulators
  • Organic Anion Transporters
  • Piperidines
  • Protein Isoforms
  • Recombinant Proteins
  • bilastine