Membrane transporters in drug development

By Kathleen M. Giacomini, Shiew-Mei Huang, D. Tweedie, L. Benet, K. Brouwer, X. Chu, A. Dahlin, R. Evers, V. Fischer, K. Hillgren and 14 more. Nature reviews. Drug discovery, 2010

3,256 citations recorded by the source corpus.

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Subfields: Infectious Diseases, Oncology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/574e15e7f17b99e67dbe53009b4e0a0eab1cfad6

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Citations in the corpus

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, positive): “…compounds including conjugated and unconjugated bile acids, bilirubin, bromosulfophthalein, neutral steroids, peptides and organic cations (Hagenbuch and Gui 2008; Kalliokoski and Niemi 2009; Kusuhara and Sugiyama 2009; Fahrmayr et al. 2010; Giacomini et al. 2010; Konig 2011; Roth et al. 2012).”
Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake (2011, background): “More than 400 membrane transporters in two major superfamilies, ATP-binding cassette and solute carrier, have been annotated in the human genome (Giacomini et al., 2010).”
Coexistence of passive and carrier-mediated processes in drug transport (2010, background): “Typical drugs used for these investigations (the number in the parentheses is oral Fa in humans): acebutolol (80–90), acetaminophen (80), acetylsalicylic acid (84–100), acyclovir (20–23), allopurinol (90), alprenolol (93–96), amiloride (50), ampicillin (62), antipyrine (97), atenolol (50–54), aztreo”
A Comprehensive Review of Drug–Drug Interactions with Metformin (2015, neutral): “1 [28].”
Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors (2017, methodology): “…in the presence of an inhibitor, ascertain the identification of COMT inhibitors as P-gp and/or BCRP substrates in accordance with the decision trees provided by the International Transporter Consortium and Food and Drug Administration (Giacomini et al., 2010; Food and Drug Administration, 2012).”
Autophagy and multidrug resistance in cancer (2017, background): “the main transporters [30]; (2) reducing drug uptake by influx transporters, such as solute carriers [31]; (3) boosting drug metabolism, including elimination by glutathione S-transferase and cytochrome P450 enzymes [32, 33]; (4) blocking apoptotic signaling pathways due to change in the expression ”