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| 2. |
- Chen, Eugene C., et al.
(författare)
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High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3
- 2022
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 39:7, s. 1599-1613
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The organic cation transporter 3 (OCT3, SLC22A3) is ubiquitously expressed and interacts with a wide array of compounds including endogenous molecules, environmental toxins and prescription drugs. Understudied as a determinant of pharmacokinetics and pharmacodynamics, OCT3 has the potential to be a major determinant of drug absorption and disposition and to be a target for drug-drug interactions (DDIs).Goal The goal of the current study was to identify prescription drug inhibitors of OCT3.Methods We screened a compound library consisting of 2556 prescription drugs, bioactive molecules, and natural products using a high throughput assay in HEK-293 cells stably expressing OCT3.Results We identified 210 compounds that at 20 mu M inhibit 50% or more of OCT3-mediated uptake of 4-Di-1-ASP (2 mu M). Of these, nine were predicted to inhibit the transporter at clinically relevant unbound plasma concentrations. A Structure-Activity Relationship (SAR) model included molecular descriptors that could discriminate between inhibitors and non-inhibitors of OCT3 and was used to identify additional OCT3 inhibitors. Proteomics of human brain microvessels (BMVs) indicated that OCT3 is the highest expressed OCT in the human blood-brain barrier (BBB).Conclusions This study represents the largest screen to identify prescription drug inhibitors of OCT3. Several are sufficiently potent to inhibit the transporter at therapeutic unbound plasma levels, potentially leading to DDIs or off-target pharmacologic effects.
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| 3. |
- Galetin, Aleksandra, et al.
(författare)
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Membrane transporters in drug development and as determinants of precision medicine
- 2024
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Ingår i: NATURE REVIEWS DRUG DISCOVERY. - 1474-1776 .- 1474-1784.
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Forskningsöversikt (refereegranskat)abstract
- The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions. Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
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| 4. |
- Giacomini, K. M., et al.
(författare)
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New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook from the International Transporter Consortium
- 2022
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Ingår i: Clinical Pharmacology & Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 112:3, s. 540-561
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Tidskriftsartikel (refereegranskat)abstract
- Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state-of-the-art article is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational, and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the solute carrier (SLC) and ATP binding cassette superfamilies, which has been enabled by the development of cryogenic electron microscopy methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research, which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function, such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which may enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue-derived small extracellular vesicles and real-world biomarkers.
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| 5. |
- Guo, Yingying, et al.
(författare)
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Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 104:5, s. 865-889
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Forskningsöversikt (refereegranskat)abstract
- This white paper examines recent progress, applications, and challenges in predicting unbound and total tissue and intra/subcellular drug concentrations using in vitro and preclinical models, imaging techniques, and physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, and case studies illustrate the application of different types of data in drug development to support modeling and decision making for compounds with transporter-mediated disposition, and likely disconnects between tissue and systemic drug exposure. The goals of this article are to illustrate current best practices and outline practical strategies for selecting appropriate in vitro and in vivo experimental methods to estimate or predict tissue and plasma concentrations, and to use these data in the application of PBPK modeling for human pharmacokinetic (PK), efficacy, and safety assessment in drug development.
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| 6. |
- Karlgren, M., et al.
(författare)
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CHAPTER 7: OATPs: The SLCO Family of Organic Anion Transporting Polypeptide Transporters
- 2021
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Ingår i: The Medicinal Chemist’s Guide to Solving ADMET Challenges. Patrick Schnider (red.). - : Royal Society of Chemistry. - 2041-3203. - 9781788012270 ; , s. 143-159
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The organic anion transporting polypeptides (OATP/SLCO) belong to the solute carrier (SLC) transporter superfamily and primarily mediate cellular uptake of anionic substrates in diverse tissues, including the liver, small intestines, kidneys and blood-brain barrier. This chapter summarizes current knowledge about the function of OATP transporters, their preclinical characterization, and the structural determinants of OATP-mediated drug transport and drug-drug interactions with a focus on the liver-specific transporters OATP1B1 and OATP1B3. © The Royal Society of Chemistry 2021.
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| 7. |
- Koziolek, M., et al.
(författare)
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Challenges in Permeability Assessment for Oral Drug Product Development
- 2023
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed.
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| 8. |
- Mateus, André, 1986-, et al.
(författare)
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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:30, s. E6231-E6239
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
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| 9. |
- Matsson, Pär, 1978-
(författare)
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ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms. The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases. To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.
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| 10. |
- Matsson, Pär, 1978, et al.
(författare)
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CHAPTER 6: OATs and OCTs: The SLC22 Family of Organic Anion and Cation Transporters
- 2021
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Ingår i: The Medicinal Chemist’s Guide to Solving ADMET Challenges. Patrick Schnider (red.). - : Royal Society of Chemistry. - 2041-3203. - 9781788012270 ; , s. 128-142
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The SLC22 transporters belong to the solute carrier (SLC) transporter superfamily and have diverse functions and expression patterns that include the cellular uptake of organic cations, anions and zwitterions in the liver and kidneys. Important members from a pharmacokinetic perspective include the organic anion transporters 1-3 (OAT1-3) and the organic cation transporters 1 and 2 (OCT1 and OCT2). This chapter summarizes current knowledge about the function of OATs and OCTs, their preclinical characterization and the structural determinants of OAT- and OCT-mediated drug transport and drug-drug interactions. © The Royal Society of Chemistry 2021.
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