| 1. |
- Ahlin, Gustav, et al.
(författare)
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Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
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Tidskriftsartikel (refereegranskat)abstract
- The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
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| 2. |
- Artursson, Per, et al.
(författare)
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Absorption Prediction
- 2004
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Ingår i: Profiling in Drug Discovery for Lead Selection. - : AAPS Press, Arlington VA.
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Bokkapitel (refereegranskat)
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| 3. |
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| 4. |
- 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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| 5. |
- Chu, X., et al.
(författare)
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Intracellular Drug Concentrations and Transporters : Measurement, Modeling, and Implications for the Liver
- 2013
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 94:1, s. 126-141
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Forskningsöversikt (refereegranskat)abstract
- Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- Hesselson, Stephanie E, et al.
(författare)
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Genetic variation in the proximal promoter of ABC and SLC superfamilies : liver and kidney specific expression and promoter activity predict variation
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:9, s. e6942-
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Tidskriftsartikel (refereegranskat)abstract
- Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (-250 to +50 bp) and flanking 5' sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (pi) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.
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| 10. |
- 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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