Article
Chemistry, Medicinal
Edward Price, J. Cory Kalvass, David DeGoey, Balakrishna Hosmane, Stella Doktor, Kelly Desino
Summary: This study evaluated different models for predicting human intestinal absorption data, providing a resource for DMPK scientists and medicinal/computational chemists to enhance their understanding of the utility and applications of permeability and absorption models for academia and industry.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Lei Zhang, Biwei Ye, Yunfeng Lin, Yi-Dong Li, Jing-Quan Wang, Zhuo Chen, Feng-Feng Ping, Zhe-Sheng Chen
Summary: In this study, the researchers investigated the effect of the CDK4/6 inhibitor, ribociclib, on multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) in human epidermoid carcinoma cells. They found that ribociclib increased the efficacy of a P-gp substrate drug, colchicine, by down-regulating the expression of P-gp and increasing its ATPase activity. Docking studies suggested that ribociclib interacted with the drug-substrate binding site of P-gp. Additionally, ribociclib inhibited the drug efflux activity of P-gp, leading to increased intracellular accumulation of doxorubicin. These findings suggest that ribociclib may be a potential agent for combined therapy in cancers with P-gp-mediated MDR.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Livio Racane, Maja Cindric, Ivo Zlatar, Tatjana Kezele, Astrid Milic, Karmen Brajsa, Marijana Hranjec
Summary: Newly synthesised benzimidazole/benzothiazole derivatives were evaluated for potential antitumor activity in vitro, with benzothiazole compounds showing higher activity compared to benzimidazole analogues. The compounds exhibited a similar mode of action on A549 cells as the standard doxorubicin. ADME analysis revealed that one active benzimidazole derivative had lower lipophilicity and higher metabolic instability. No significant differences were observed in ADME profiles between active and non-active compounds.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Michika Murata, Hijiri Fujioka, Jumpei Yokota, Kentaro Okada, Tomoki Yamashita, Daisuke Hirayama, Kentaro Kawakami, Gaku Morinaga, Asami Saito, Hiroshi Nakase, Wataru Kishimoto, Hiroyuki Mizuguchi
Summary: In this study, the expression profiles of drug absorption, distribution, metabolism, and excretion (ADME)-related genes in different regions of the human intestine were analyzed. The results showed significant differences in gene expression between the small and large intestines, particularly for CYP enzymes.
MOLECULAR PHARMACEUTICS
(2023)
Review
Pharmacology & Pharmacy
Marit Keuper-Navis, Markus Walles, Birk Poller, Adam Myszczyszyn, Thomas K. van der Made, Joanne Donkers, Hossein Eslami Amirabadi, Martijn J. Wilmer, Saskia Aan, Bart Spee, Rosalinde Masereeuw, Evita van de Steeg
Summary: Organ-on-chip (OoC) technology has the potential to improve the prediction of human oral bioavailability and intrinsic clearance. This review discusses the functionality and application of OoC models in current drug development practice, and summarizes the use of multi-OoC models for pharmacokinetic (PK) studies. Challenges and recommended parameters for a minimal viable platform of a multi-OoC model are provided. The translation to in vivo PK profiles is also discussed, which is essential for routine application of OoC models in drug development.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Stefania Olla, Maristella Steri, Alessia Formato, Michael B. Whalen, Silvia Corbisiero, Cristina Agresti
Summary: Oxidative stress is implicated in the pathogenesis of multiple sclerosis (MS), and identifying drugs that can regulate oxidative homeostasis may offer new treatment options for the disease. This study used an in silico approach to link genome-wide MS associations and molecular QTLs to explore potential drug targets related to oxidative stress pathways. The findings suggest existing drugs could target OS-related molecules regulated by functional MS variants, in addition to approved disease-modifying treatments.
Article
Chemistry, Medicinal
Franco Lombardo, Jorg Bentzien, Giuliano Berellini, Ingo Muegge
Summary: A novel descriptor-parsimonious in silico model has been developed to predict human VDss and shown to perform on par with a former benchmark model based on more descriptors, allowing for interpretations essential for compound design. The in silico approach is supported by comparisons with in vitro derived descriptors or in vivo scaling methods due to its resource- and animalsparing nature. The strong performance of in silico VDss models on structurally novel compounds indicates high confidence in using in silico human VDss predictions for compound design and human dose predictions.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemical Research Methods
Amit Kumar Sahu, Tarang Jadav, Niraj Rajput, Manish Kumar Sharma, Pinaki Sengupta
Summary: This study developed quantitative bioanalytical methods for RIBO and OLA, and reported, for the first time, the drug-drug interaction potential between RIBO and OLA.
Article
Pharmacology & Pharmacy
Christine Huynh, Swen Seeland, Jerome Segrestaa, Carmela Gnerre, Jens Hogeback, Henriette E. Meyer zu Schwabedissen, Jasper Dingemanse, Patricia N. Sidharta
Summary: This study reports the metabolites and metabolic pathways of the CXCR7 antagonist ACT-1004-1239. The major enzyme involved in the metabolism of ACT-1004-1239 was identified as CYP3A4 in vitro, and the primary elimination pathway in humans was through the metabolite M1.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yongjie Zhang, Jie Xu, Jie Zhao, Huili Chen, Ning Li, Xijing Chen, Di Zhao
Summary: This study used ICP-MS and stable isotope labeling strategy to systematically investigate the pharmacokinetic properties of Hemin. The results showed that Hemin was rapidly absorbed in the gastrointestinal tract and distributed to various organs, with predominant excretion via feces. The majority of Hemin in plasma was found to be bound to proteins.
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
(2023)
Review
Pharmacology & Pharmacy
Tridib Chaira, Chandru Subramani, Tarani Kanta Barman
Summary: The search for new drugs is time-consuming and expensive, with a significant portion of resources dedicated to generating predictive human pharmacokinetic profiles from animal data. These profiles are crucial for optimizing antiviral drug research and extrapolating human pharmacokinetic parameters from animal profiles.
Article
Oncology
Gabrielle van Caloen, Sandra Schmitz, Cedric van Marcke, Xavier Caignet, Antonella Mendola, Sebastien Pyr Dit Ruys, Pierre P. Roger, Didier Vertommen, Jean-Pascal Machiels
Summary: The combination of cetuximab and ribociclib was not significantly more effective than cetuximab monotherapy in HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. In addition, the combination of cetuximab and ribociclib may reduce the activity of the CDK4/6 inhibitor in cetuximab-resistant models. The downregulation of the retinoblastoma (Rb) protein was observed in cetuximab-treated mice, suggesting potential mechanisms for cetuximab resistance.
Article
Oncology
Sofia Schaeffer, Christian Lutz, Michael Dobbie, Luigi M. Terracciano, Matthias Matter, Jurg Vosbeck, Markus H. Heim, Christine Bernsmeier
Summary: This case report describes a severe idiosyncratic hepatocellular pattern drug-induced liver injury (DILI) induced by ribociclib in a patient with HR-positive, HER2-negative breast cancer. Liver enzyme elevation occurred during treatment and a liver biopsy showed acute hepatitis with parenchymal necrosis. Corticosteroid treatment and N-acetylcysteine were effective in normalizing liver enzymes.
FRONTIERS IN ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Vani Vemula, Amarnath Satheesh Marudamuthu, Sanjay Prasad, B. M. Suman, S. E. Mamatha, A. Swathi, Priyanka Seal, Manikandan Alagumuthu
Summary: The main objective of this study was to screen potential small molecule inhibitors against HPV16 E6 protein using a fragment-based approach. Twenty-six natural HPV inhibitors were selected and used to generate novel inhibitors. The top three compounds, Cpd5, Cpd7, and Cpd10, showed high potency as HPV16 E6P inhibitors and had favorable absorption and drug-likeness characteristics. These compounds have the potential to be developed as new drugs for HPV-related diseases.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Oncology
Sara M. Tolaney, Young-Hyuck Im, Emiliano Calvo, Yen-Shen Lu, Erika Hamilton, Andres Forero-Torres, Thomas Bachelot, Michela Maur, Angelica Fasolo, Ralph Tiedt, Lisa Nardi, Uz Stammberger, Ahmed M. Abdelhady, Shiling Ruan, Soo Chin Lee
Summary: The study evaluated the safety and tolerability of dual inhibition of the CDK4/6 and PI3K pathways in patients with HR+, HER2(-) ABC, showing that the combination of ribociclib and fulvestrant is safe for treatment. However, triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for further investigation.
CLINICAL CANCER RESEARCH
(2021)