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Publications (10 of 28) Show all publications
Guo, Y., Chu, X., Parrott, N. J., Brouwer, K. L. R., Hsu, V., Nagar, S., . . . Galetin, A. (2018). Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clinical Pharmacology and Therapeutics, 104(5), 865-889
Open this publication in new window or tab >>Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 5, p. 865-889Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-369941 (URN)10.1002/cpt.1183 (DOI)000448068500014 ()30059145 (PubMedID)
Funder
NIH (National Institute of Health), R01 GM041935, R35 GM122576, 1R01GM104178, 1R01GM114369, DA P01DA032507
Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2018-12-18Bibliographically approved
Sebastiano, M. R., Doak, B. C., Backlund, M., Poongavanam, V., Over, B., Ermondi, G., . . . Kihlberg, J. (2018). Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5. Journal of Medicinal Chemistry, 61(9), 4189-4202
Open this publication in new window or tab >>Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4189-4202Article in journal (Refereed) Published
Abstract [en]

Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds’ minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing “chameleonic” properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-356490 (URN)10.1021/acs.jmedchem.8b00347 (DOI)000432204800029 ()29608068 (PubMedID)
Funder
Åke Wiberg FoundationMagnus Bergvall Foundation
Available from: 2018-07-30 Created: 2018-07-30 Last updated: 2018-07-30Bibliographically approved
Treyer, A., Mateus, A., Wisniewski, J. R., Boriss, H., Matsson, P. & Artursson, P. (2018). Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids. Molecular Pharmaceutics, 15(6), 2224-2233
Open this publication in new window or tab >>Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 6, p. 2224-2233Article in journal (Refereed) Published
Abstract [en]

Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability (F-ic) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower F-ic. The induction of NL did not further increase drug binding but led to altered F-ic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
Keywords
intracellular drug bioavailability, lipid, phospholipid, drug binding membrane partitioning, proteomics, 3T3-L1, unbound concentration
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-358082 (URN)10.1021/acs.molpharmaceut.8b00064 (DOI)000434491800015 ()29709195 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 60751Swedish Research Council, 2822Swedish Research Council, 2017-01951Åke Wiberg Foundation
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-12-18Bibliographically approved
Schlessinger, A., Welch, M. A., van Vlijmen, H., Korzekwa, K., Swaan, P. W. & Matsson, P. (2018). Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective. Clinical Pharmacology and Therapeutics, 104(5), 818-835
Open this publication in new window or tab >>Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective
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2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 5, p. 818-835Article, review/survey (Refereed) Published
Abstract [en]

Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy. Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs(1-4); further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches.(5,6) Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug-drug interactions (DDIs).(5,6)

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-369940 (URN)10.1002/cpt.1174 (DOI)000448068500012 ()29981151 (PubMedID)
Funder
NIH (National Institute of Health), R01 GM108911, R01 DK061425Åke Wiberg Foundation
Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2018-12-18Bibliographically approved
Matsson, P. & Kihlberg, J. (2017). How Big Is Too Big for Cell Permeability?. Journal of Medicinal Chemistry, 60(5), 1662-1664
Open this publication in new window or tab >>How Big Is Too Big for Cell Permeability?
2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 5, p. 1662-1664Article in journal (Refereed) Published
Abstract [en]

Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-319534 (URN)10.1021/acs.jmedchem7b00237 (DOI)000396296100005 ()28234469 (PubMedID)
Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-07-30Bibliographically approved
Mateus, A., Treyer, A., Wegler, C., Karlgren, M., Matsson, P. & Artursson, P. (2017). Intracellular drug bioavailability: a new predictor of system dependent drug disposition. Scientific Reports, 7, 1-12, Article ID 43047.
Open this publication in new window or tab >>Intracellular drug bioavailability: a new predictor of system dependent drug disposition
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-12, article id 43047Article in journal (Refereed) Published
Abstract [en]

Intracellular drug exposure is influenced by cell-and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (F-ic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Fic of its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that Fic provides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-317940 (URN)10.1038/srep43047 (DOI)000394530900001 ()28225057 (PubMedID)
Available from: 2017-04-01 Created: 2017-04-01 Last updated: 2019-07-23Bibliographically approved
Mateus, A., Gordon, L. J., Wayne, G. J., Almqvist, H., Axelsson, H., Seashore-Ludlow, B., . . . Artursson, P. (2017). Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery. Proceedings of the National Academy of Sciences of the United States of America, 114(30), E6231-E6239
Open this publication in new window or tab >>Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 30, p. E6231-E6239Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2017
Keywords
intracellular drug bioavailability, drug exposure, target engagement, published kinase inhibitor set, MAPK14
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-332843 (URN)10.1073/pnas.1701848114 (DOI)000406189900026 ()28701380 (PubMedID)
Funder
Swedish Research Council, 2822Carl Tryggers foundation Magnus Bergvall FoundationÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, FP7, Seventh Framework Programme, 607517
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2018-07-30Bibliographically approved
Matsson, P., Doak, B. C., Over, B. & Kihlberg, J. (2016). Cell permeability beyond the rule of 5. Advanced Drug Delivery Reviews, 101, 42-61
Open this publication in new window or tab >>Cell permeability beyond the rule of 5
2016 (English)In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 42-61Article, review/survey (Refereed) Published
Abstract [en]

Drug discovery for difficult targets that have large and flat binding sites is often better suited to compounds beyond the "rule of 5" (bRo5). However, such compounds carry higher pharmacokinetic risks, such as low solubility and permeability, and increased efflux and metabolism. Interestingly, recent drug approvals and studies suggest that cell permeable and orally bioavailable drugs can be discovered far into bRo5 space. Tactics such as reduction or shielding of polarity by N-methylation, bulky side chains and intramolecular hydrogen bonds may be used to increase cell permeability in this space, but often results in decreased solubility. Conformationally flexible compounds can, however, combine high permeability and solubility, properties that are keys for cell permeability and intestinal absorption. Recent developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability. Transporter mediated efflux occurs for most investigated drugs in bRo5 space, however it is commonly overcome by high local intestinal concentrations on oral administration. In contrast, there is little data to support significant impact of transporter-mediated intestinal absorption in bRo5 space. Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies.

Keywords
Beyond the rule of 5, Permeability, Conformational shielding, Intramolecular hydrogen bonds, Macrocycles, Cyclic peptides, Efflux transporters, Quantitative structure permeability relationships
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-300382 (URN)10.1016/j.addr.2016.03.013 (DOI)000378667800005 ()27067608 (PubMedID)
Funder
Carl Tryggers foundation AstraZeneca
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2018-07-30Bibliographically approved
Over, B., Matsson, P., Tyrchan, C., Artursson, P., Doak, B. C., Foley, M. A., . . . Kihlberg, J. (2016). Structural and conformational determinants of macrocycle cell permeability. Nature Chemical Biology, 12(12), 1065-+
Open this publication in new window or tab >>Structural and conformational determinants of macrocycle cell permeability
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2016 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, p. 1065-+Article in journal (Refereed) Published
Abstract [en]

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-311178 (URN)10.1038/NCHEMBIO.2203 (DOI)000388582900016 ()27748751 (PubMedID)
Funder
AstraZenecaCarl Tryggers foundation Swedish Research Council, 2822
Note

Delat förstaförfattarskap: Bjorn Over, Pär Matsson

(Shared first authorship: Bjorn Over, Pär Matsson)

Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-07-30
Matsson, P. X., Lundquist, P. & Artursson, P. (2016). The Need for Speed-Kinetic Limits of Drug Transporters [Letter to the editor]. TIPS - Trends in Pharmacological Sciences, 37(4), 243-245
Open this publication in new window or tab >>The Need for Speed-Kinetic Limits of Drug Transporters
2016 (English)In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 37, no 4, p. 243-245Article in journal, Letter (Refereed) Published
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-299391 (URN)10.1016/j.tips.2016.02.002 (DOI)000374708300001 ()26922253 (PubMedID)
Available from: 2016-07-18 Created: 2016-07-18 Last updated: 2018-07-30Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-9094-2581

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