Review
Pharmacology & Pharmacy
Khalid Rashid, Aqeel Ahmad, Li Liang, Mengling Liu, Yuehong Cui, Tianshu Liu
Summary: Solute carrier (SLC) transporters play diverse roles in tumor modulation, not only through influx/efflux mechanisms but also by activating signaling network cascades that drive metastatic tumor formation. However, further research is needed to fully understand the implications of these proteins in cancer pathogenesis.
DRUG DISCOVERY TODAY
(2021)
Article
Chemistry, Medicinal
Katherine D. Lynch, Michelle L. Montonye, Dan-Dan Tian, Tarana Arman, Victoria O. Oyanna, Baron J. Bechtold, Tyler N. Graf, Nicholas H. Oberlies, Mary F. Paine, John D. Clarke
Summary: Silymarin, derived from milk thistle seeds, contains flavonolignans that are substrates for OATPs/Oatps. Research shows that OATPs/Oatps play a role in flavonolignan cellular uptake, and mediate interactions between silymarin and diseases like NASH on drug exposure.
PHYTOTHERAPY RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Yun Ju Kang, Chul Haeng Lee, Soo-Jin Park, Hye Suk Lee, Min-Koo Choi, Im-Sook Song
Summary: The study found that OAT1 and OAT3 are important transporters that may regulate the pharmacokinetic properties of rosmarinic acid and potentially cause herb-drug interactions with the compound.
Article
Pharmacology & Pharmacy
Philip Sandoval, Bei-Ching Chuang, John K. Fallon, Philip C. Smith, Swapan K. Chowdhury, Robert J. Griffin, Cindy Q. Xia, Shinji Iwasaki, Paresh P. Chothe
Summary: The liver plays a central role in the elimination of drugs from the body, and understanding the processes involved is crucial for accurately assessing hepatic drug clearance. This study focused on the hepatobiliary disposition of a synthetic STING agonist called ML00960317. The results showed that biliary excretion is the primary route of elimination for ML00960317, with OATP1B1, OATP1B3, and MRP2 playing a significant role in its transport. The findings suggest that these pathways may have a major influence on the hepatic clearance of ML00960317 and pose a potential risk for drug-drug interactions.
Article
Chemistry, Multidisciplinary
Lu-lu Pan, Yong Yang, Min Hui, Shuo Wang, Cui-yun Li, Hong Zhang, Yan-hua Ding, Li Fu, Xing-xing Diao, Da-fang Zhong
Summary: This study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans, and determine the major enzymes and transporters involved in these processes. The research found that sulfation dominated the metabolism and pharmacokinetics of forsythin, with the sulfate conjugate being excreted mainly in the urine. Sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were identified as the most active hepatic enzymes involved in the formation of specific metabolites.
ACTA PHARMACOLOGICA SINICA
(2021)
Article
Oncology
Shunji Takahashi, Masato Karayama, Masato Takahashi, Junichiro Watanabe, Hironobu Minami, Noboru Yamamoto, Ichiro Kinoshita, Chia-Chi Lin, Young-Hyuck Im, Issei Achiwa, Emi Kamiyama, Yasuyuki Okuda, Caleb Lee, Yung-Jue Bang
Summary: In this study, it was found that the combination of trastuzumab deruxtecan with ritonavir or itraconazole did not have a significant impact on the pharmacokinetics of the drug, with good safety profile and promising antitumor activity demonstrated.
CLINICAL CANCER RESEARCH
(2021)
Article
Chemistry, Medicinal
Youmna Ali, Tahiatul Shams, Zhengqi Cheng, Yue Li, Chelsea Siu-Wai Chun, Wenying Shu, Xiaofeng Bao, Ling Zhu, Michael Murray, Fanfan Zhou
Summary: This study evaluated the regulatory actions of Wnt inhibitors on human renal Organic anion transporters and Organic anion transporting polypeptides, showing that these inhibitors significantly decrease the activities and membrane expression of multiple transporters. The findings suggest that Wnt inhibitors may have unexpected effects on drug entry into cells.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Chunxu Ni, Xuyang Wang, Jie Chen, Su Xu, Wenjing Ye, Mei Hong
Summary: In this study, it was found that the leucine heptad repeats within the transmembrane domains of OATP1B1 play crucial roles in its function and protein-protein interactions, with disruption of the repeats in TM3 significantly reducing OATP1B1's uptake function.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Biochemistry & Molecular Biology
Dan-Dan Wang, Yan Li, Yi-Jin Wu, Yi-Lai Wu, Jun Han, Opeyemi Joshua Olatunji, Li Wang, Jian Zuo
Summary: This study found that xanthones derived from Securidaca inappendiculata antagonized the anti-rheumatic effects of MTX in vivo, reducing MTX concentration and promoting its excretion, resulting in hindered renal excretion of MTX. In vitro assays also showed that xanthones can enhance the cellular intake of MTX.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Fangrui Xiu, Magdalena Rausch, Zhibo Gai, Shanshan Su, Shijun Wang, Michele Visentin
Summary: Tyrosine kinase inhibitors (TKIs) have made decisive contributions in revolutionizing cancer therapy by offering non-invasive and tolerable treatments for improved quality of life. However, the efficacy and durability of TKI therapy can vary due to factors such as cancer molecular features, drug resistance, pharmacokinetic alterations caused by genetic variants, and unwanted drug interactions. This article reviews the interactions between TKIs and organic cation transporters (OCTs) in vitro and in vivo, and discusses their potential clinical implications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Elizabeth Cooper, Zoe Woolf, Molly E. Swanson, Jason Correia, Patrick Schweder, Edward Mee, Peter Heppner, Clinton Turner, Richard L. M. Faull, Emma L. Scotter, William A. Denny, Peter J. Choi, Mike Dragunow, Jiney Jose, Thomas I-H Park
Summary: This study demonstrates, for the first time, the expression of four OATP isoforms in human GBM tissue, with upregulation within the tumor microenvironment by myeloid cells and tumor vasculature, as well as isoform-specific upregulation within hypoxic niches.
NEURO-ONCOLOGY ADVANCES
(2022)
Article
Pharmacology & Pharmacy
Wenyan Li, Zheng Jiao, Yanhui Liu, Jiacheng Yao, Guodong Li, Jing Dong
Summary: The study evaluated the renal excretion mechanism of Biapenem and its interactions with other drugs, indicating that it is primarily eliminated through glomerular filtration with minimal OAT3-mediated renal tubular secretion. Biapenem has low affinity for OAT3 and can be safely used with other drugs that act as substrates or inhibitors of OAT3.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Santosh Kumar Adla, Arun Kumar Tonduru, Thales Kronenberger, Eva Kudova, Antti Poso, Kristiina M. Huttunen
Summary: In this study, synthetic neurosteroids were delivered into MCF-7 cells via OATPs to investigate structural components necessary for cellular uptake and understand brain drug delivery. The research identified key structural features that improve the affinity of neurosteroids and interact with specific amino acids, providing insights for potential drug delivery strategies across the blood-brain barrier.
Review
Pharmacology & Pharmacy
Jonny Kinzi, Markus Grube, Henriette E. Meyer zu Schwabedissen
Summary: OATP2B1 plays a significant role in oral drug absorption, but pharmacogenetic findings are inconclusive.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Md Masud Parvez, Said Kalkisim, Phuong Thi Thu Nguyen, Jin Ah Jung, Jeong-Kon Park, Jong-Lyul Ghim, Eun-Young Kim, Yong-Soon Cho, Melih O. Babaoglu, Jae-Gook Shin
Summary: The study investigated the drug-drug interaction between PAS and Tenofovir, showing that PAS-Ca formulation significantly reduced systemic exposure to Tenofovir. Clinical trials are necessary to validate the accuracy of in vitro data when studying drug interactions.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Sophie J. Bradley, Colin Molloy, Christoffer Bundgaard, Adrian J. Mogg, Karen J. Thompson, Louis Dwomoh, Helen E. Sanger, Michael D. Crabtree, Simon M. Brooke, Patrick M. Sexton, Christian C. Felder, Arthur Christopoulos, Lisa M. Broad, Andrew B. Tobin, Christopher J. Langmead
MOLECULAR PHARMACOLOGY
(2018)
Article
Neurosciences
Kai-Chun Yang, Vladimir Stepanov, Nahid Amini, Stefan Martinsson, Akihiro Takano, Christoffer Bundgaard, Benny Bang-Andersen, Connie Sanchez, Christer Halldin, Lars Farde, Sjoerd J. Finnema
NEUROPSYCHOPHARMACOLOGY
(2019)
Article
Multidisciplinary Sciences
Christina Birkedahl Falk-Petersen, Tsonko M. Tsonkov, Malene Sofie Nielsen, Kasper Harpsoe, Christoffer Bundgaard, Bente Frolund, Uffe Kristiansen, David E. Gloriam, Petrine Wellendorph
SCIENTIFIC REPORTS
(2020)
Article
Pharmacology & Pharmacy
Lassina Badolo, Kenneth Thirstrup, Soren Moller Nielsen, Ask Puschl, Thomas Jensen, Steve Watson, Christoffer Bundgaard
Article
Behavioral Sciences
Zackary A. Cope, Johnny A. Kenton, Arpi Minassian, Maureen V. Martin, William Perry, Christoffer Bundgaard, Jorn Arnt, Jordy van Enkhuizen, Mark A. Geyer, Jared W. Young
Summary: The study highlights the different responses of DAT knockdown mice to risperidone and asenapine in mania behavior, pointing out the limitations of current treatment methods, and further emphasizes the necessity of resources and research into DAT-targeting drugs.
BEHAVIOURAL BRAIN RESEARCH
(2021)
Article
Clinical Neurology
Yasmine Iacone, Tatiana P. Morais, Francois David, Francis Delicata, Joanna Sandle, Timea Raffai, Harri Rheinallt Parri, Johan Juhl Weisser, Christoffer Bundgaard, Ib Vestergaard Klewe, Gabor Tamas, Morten Skott Thomsen, Vincenzo Crunelli, Magor L. Lorincz
Summary: Oral administration of ivabradine significantly reduced ASs in a dose-dependent manner. Ivabradine injection into CIN abolished ASs and induced small-amplitude 4-7Hz waves, while its effect in the VB was less potent. Additionally, application of ivabradine to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. These findings suggest that systemically administered HCN channel blockers may serve as a novel therapeutic approach for ASs.
Article
Biochemistry & Molecular Biology
Alastair J. H. Brown, Sophie J. Bradley, Fiona H. Marshall, Giles A. Bown, Kirstie A. Bennett, Jason Brown, Julie E. Cansfield, David M. Cross, Chris de Graaf, Brian D. Hudson, Louis Dwomoh, Joao M. Dias, James C. Errey, Edward Hurrell, Jan Liptrot, Giulio Mattedi, Colin Molloy, Pradeep J. Nathan, Krzysztof Okrasa, Greg Osborne, Jayesh C. Patel, Mark Pickworth, Nathan Robertson, Shahram Shahabi, Christoffer Bundgaard, Keith Phillips, Lisa M. Broad, Anushka V. Goonawardena, Stephen R. Morairty, Michael Browning, Francesca Perini, Gerard R. Dawson, John F. W. Deakin, Robert T. Smith, Patrick M. Sexton, Julie Warneck, Mary Vinson, Tim Tasker, Benjamin G. Tehan, Barry Teobald, Arthur Christopoulos, Christopher J. Langmead, Ali Jazayeri, Robert M. Cooke, Prakash Rucktooa, Miles S. Congreve, Malcolm Weir, Andrew B. Tobin
Summary: The study aims to design a well-tolerated M1 agonist with the potential to alleviate cognitive loss by translating from atomic structure to clinical trials, providing a strategy for targeting difficult GPCR targets effectively.
Article
Chemistry, Medicinal
Francesco Bavo, Heleen De-Jong, Jonas Petersen, Christina Birkedahl Falk-Petersen, Rebekka Loeffler, Emma Sparrow, Frederik Rostrup, Jannik Nicklas Eliasen, Kristine S. Wilhelmsen, Kasper Barslund, Christoffer Bundgaard, Birgitte Nielsen, Uffe Kristiansen, Petrine Wellendorph, Yury Bogdanov, Bente Frolund
Summary: The study identified the structural determinants of 2027 and suggested a potential binding mode. The structurally simplified m-methylphenyl analog 1e displayed high-nanomolar range binding affinity and potential application in peripheral GABAAR inhibition.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Andrea Varrone, Christoffer Bundgaard, Benny Bang-Andersen
Summary: In central nervous system drug discovery, PET is a crucial tool for assessing the distribution and binding of new chemical entities in the brain. This review summarizes the main applications of PET in early drug development and proposes aligned nomenclatures for key pharmacokinetic parameters to guide PET studies.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Chemistry, Medicinal
Yongsong Tian, Mohamed A. Shehata, Stine Juul Gauger, Clarissa K. L. Ng, Sara Solbak, Louise Thiesen, Jesper Bruus-Jensen, Jacob Krall, Christoffer Bundgaard, K. Michael Gibson, Petrine Wellendorph, Bente Frolund
Summary: This study identified the CaMKIIα hub domain as a high-affinity target and synthesized a series of analogues, with the oxygen-bridged analogue 4d showing promising affinity and stability, making it a potential drug candidate with enhanced pharmacokinetic properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Irena Loryan, Andreas Reichel, Bo Feng, Christoffer Bundgaard, Christopher Shaffer, Cory Kalvass, Dallas Bednarczyk, Denise Morrison, Dominique Lesuisse, Edmund Hoppe, Georg C. Terstappen, Holger Fischer, Li Di, Nicola Colclough, Scott Summerfield, Stephen T. Buckley, Tristan S. Maurer, Markus Friden
Summary: The unbound brain-to-plasma partition coefficient (K-p, K-uu, K-brain) plays a crucial role in pharmacological responses and has been widely applied in drug discovery and development.
PHARMACEUTICAL RESEARCH
(2022)
Article
Biochemical Research Methods
Anne-Marie Jacobsen, Nico C. van de Merbel, Dorte K. Ditlevsen, Ketil Tvermosegaard, Frank Schalk, Wietske Lambert, Christoffer Bundgaard, Jan T. Pedersen, Nina Rosenqvist
Summary: A new method was developed to measure pS396-tau in cerebrospinal fluid (CSF) in humans and animal models of Alzheimer's Disease (AD). The method discriminates between phosphorylated and nonphosphorylated tau using proteolytic enzyme treatment, and allows for quantitative measurement of pS396-tau. The method was successfully validated in CSF samples from healthy controls, patients with Mild Cognitive Impairment and AD, as well as in AD mouse models.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Article
Chemistry, Medicinal
Nanna Tynelius, Christoffer Bundgaard, Claudia E. Mueller
Summary: Hepatocyte cocultures like HepatoPac have advantages in enzymatic activity over time, making them more frequently used for assessing the intrinsic clearance of slowly metabolised drugs. However, the high cost and practical limitations hinder the inclusion of quality control compounds in studies, resulting in the lack of monitoring of important metabolic enzymes. This study evaluates the use of a cocktail approach of quality control compounds in the human HepatoPac system to ensure adequate activity of major metabolising enzymes.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Kristine Langthaler, Christopher R. Jones, Birger Brodin, Christoffer Bundgaard
Summary: The application of Göttingen minipigs for non-rodent pharmacokinetics and drug safety testing has increased in recent years. This study aimed to compare the brain-to-plasma ratios of different compounds in female Göttingen minipigs with those of other species, and found that the ratios were similar between minipigs and rats. These findings contribute to the understanding of drug disposition and support the use of Göttingen minipigs as a non-rodent drug safety model and a brain PK model for clinical translation.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Kristine Langthaler, Christopher R. Jones, Rasmus B. Christensen, Elin Eneberg, Birger Brodin, Christoffer Bundgaard
Summary: This study evaluated the use of in vitro to in vivo extrapolation (IVIVE) methodologies for predicting hepatic, metabolic clearance in the Gottingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics. The results showed that regression-corrected IVIVE provided more accurate prediction of in vivo clearance and offered a practical and unified scaling approach.
Article
Pharmacology & Pharmacy
Xuezhi Zhuo, Vito Fodera, Per Larsson, Zarah Schaal, Christel A. S. Bergstrom, Korbinian Lobmann, Aleksei Kabedev
Summary: Our previous work demonstrated that beta-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for over 12 months. We further investigated the stabilization mechanisms by testing five other drug molecules and using experimental techniques and molecular dynamics simulations. The results showed that steric confinement, hydrogen bonding, and the glass transition temperature of the drug molecule play important roles in stabilizing ASDs with high drug loadings.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Sebastian Schmidt, Ulrike Holzgrabe
Summary: The binding of drugs to plasma proteins, such as human serum albumin (HSA), is crucial for determining pharmacokinetic parameters. This study investigated the enantioselective binding of S- and R-ketamine to HSA. It was found that ketamine has weak affinity to HSA, with no significant differences in binding behavior between the individual enantiomers and the racemate. The aromatic ring and N-methyl group were identified as the most strongly involved structural moieties in the binding of ketamine to HSA.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Yuchen Zhao, Han Wang, Lin Jin, Ziwei Zhang, Lianghu Liu, Mengqi Zhou, Xianzheng Zhang, Lingling Zhang
Summary: Interleukins (ILs) are important for communication between immune cells and non-immune cells, but dysregulation of ILs expression is a characteristic of autoinflammatory diseases. Drugs targeting ILs have significant clinical benefits, but may also cause adverse reactions. Fusion protein technology, with its ability to enhance therapeutic efficacy, has been explored for developing anti-inflammatory drugs. This review discusses the efficacy of fusion protein drugs developed with ILs or their receptors in treating autoinflammatory diseases, highlighting the potential of this technology in future anti-inflammatory drug development.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Serena Bertoni, Elena Simone, Stefano Sangiorgi, Beatrice Albertini, Nadia Passerini
Summary: This study investigated the correlation between the structure and release properties of solid lipid microparticles (MPs) with different liquid additives. The additives accelerated the conversion of the unstable alpha-form of tristearin to the stable beta-polymorph and caused structural modifications in the MPs. The presence of additives prolonged the drug release in water and resulted in higher release profiles in biorelevant media. The findings suggest that the release behavior can be influenced by the polymorphism and supramolecular-level structural modification of lipid formulations containing crystal modifiers.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Juulia Jarvinen, Ahmed B. Montaser, Santosh Kumar Adla, Jukka Leppanen, Marko Lehtonen, Kati-Sisko Vellonen, Tuomo Laitinen, Aaro Jalkanen, William F. Elmquist, Juri Timonen, Kristiina M. Huttunen, Jarkko Rautio
Summary: This study attempted to alter the brain distribution pattern of Palbociclib by creating and assessing two novel prodrugs. Although the prodrug design did not significantly improve Palbociclib brain delivery, the study provides valuable insights for future prodrug development and drug delivery strategies targeting specific transporters.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Review
Pharmacology & Pharmacy
Miao Wang, Xinyu Ma, Shiyu Zong, Yaqiong Su, Rui Su, Hong Zhang, Yang Liu, Chunliu Wang, Ye Li
Summary: This article discusses the potential and limitations of nasal administration in central nervous system drug delivery. Nasal gel viscosity can alleviate the impact of nasal mucociliary clearance on drug delivery, and materials such as gellan gum, chitosan, carbomer, cellulose, and poloxamer can be used to prepare nasal gels.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Bjarke Strom Larsen, Eric Kissi, Liebert Parreiras Nogueira, Natalja Genina, Ingunn Tho
Summary: This study investigates the influence of drug load and polymer molecular weight on the structure of 3D printed tablets. The results show that drug load and polymer molecular weight have a significant impact on the porosity and size of the tablets, while the effect of drug load on the total porosity of the tablets is minimal.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Zhentao Qiao, Fuhang Wang, Dongjian Han, Yuansong Zhuang, Qingjiao Jiang, Yi Zhang, Miaomiao Liu, Quanxu An, Zhiwei Wang, Deliang Shen
Summary: In this study, it was demonstrated that periadventitial delivery of rapamycin-fibrin glue (RPM-FG) can inhibit intimal hyperplasia (IH) in a rat carotid artery injury model without compromising re-endothelialization. This provides a promising direction for the future development of a safe, effective, and minimally invasive perivascular drug delivery method to treat vascular disease.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)
Article
Pharmacology & Pharmacy
Neele Puhlmann, Rodrigo Vidaurre, Klaus Kuemmerer
Summary: Active pharmaceutical ingredients and their metabolites and transformation products are pollutants that can harm human and environmental health. Designing greener APIs is an effective strategy to address this issue. The drug discovery and development process can incorporate environmental parameters to achieve this design, and this process is highly flexible.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2024)