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.
Benzimidazoles/pharmacology , Histamine H1 Antagonists, Non-Sedating/pharmacology , Membrane Transport Modulators/pharmacology , Piperidines/pharmacology , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Benzimidazoles/adverse effects , Benzimidazoles/metabolism , 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 , Humans , Membrane Transport Modulators/adverse effects , Membrane Transport Modulators/metabolism , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Osmolar Concentration , Piperidines/adverse effects , Piperidines/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Spodoptera
[reaction: see text] Alicyclic beta-lactams were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction (U-4C-3CR), starting from alicyclic beta-amino acids such as cis-2-aminocyclohexanecarboxylic acid, cis-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues. A six-membered mixture-based combinatorial library of beta-lactams was also generated.
beta-Lactams/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Indicators and Reagents , Stereoisomerism , beta-Lactams/chemistry
