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Diffusion Smart-seq3 of breast cancer spheroids to explore spatial tumor biology and test evolutionary principles of tumor heterogeneity.
Sci Rep
January 2025
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Combining 3D cultures such as tumor spheroids and organoids with spatial omics holds great potential for tissue biology and cancer research. Yet, this potential is presently limited by technical and financial challenges of spatial omics methods and 3D cultures. To address this, we combine dye diffusion, the Smart-seq3xpress protocol for deep single-cell gene expression profiling, and dedicated probabilistic inference methods into diffusion Smart-seq3 (Smart-seq3D), to reveal the transcriptome of single cells along with their position along the core-periphery axis of spheroids.
View Article and Find Full Text PDFReal-world application of physiologically based pharmacokinetic models in drug discovery.
Drug Metab Dispos
January 2025
Simcyp Division, Certara UK, Ltd, Princeton, New Jersey. Electronic address:
The utility of physiologically based pharmacokinetic (PBPK) models in support of drug development has been well documented. During the discovery stage, PBPK modeling has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection, and early formulation assessment. Previous review articles have proposed model-building and application strategies for PBPK-based first-in-human predictions with comprehensive descriptions of the individual components of PBPK models.
View Article and Find Full Text PDFImpact of genetic polymorphisms and drug-drug interactions mediated by carboxylesterase 1 on remimazolam deactivation.
Drug Metab Dispos
January 2025
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio. Electronic address:
Remimazolam (Byfavo, Acacia Pharma), a recent Food and Drug Administration-approved ester-linked benzodiazepine, offers advantages in sedation, such as rapid onset and predictable duration, making it suitable for broad anesthesia applications. Its favorable pharmacological profile is primarily attributed to rapid hydrolysis, the primary metabolism pathway for its deactivation. Thus, understanding remimazolam hydrolysis determinants is essential for optimizing its clinical use.
View Article and Find Full Text PDFUncovering the impact of COVID-19-mediated bidirectional dysregulation of cytochrome P450 3A4 on systemic and pulmonary drug concentrations using physiologically based pharmacokinetic modeling.
Drug Metab Dispos
January 2025
Current affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Current affiliation: OneDrug Inc., Toronto, Ontario, Canada; Program in Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom. Electronic address:
Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially in the lung tissue, which is most affected by the disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate the differences in systemic and pulmonary concentrations of 4 respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), and ICU patients.
View Article and Find Full Text PDFLong-Term Stabilized and Highly Soluble Bezafibrate-Gliclazide Co-Amorphous Binary System.
AAPS PharmSciTech
January 2025
School of Engineering and Sciences, Tecnologico de Monterrey, Campus Monterrey, Ave. Eugenio Garza Sada 2501 Sur, C.P. 64849, Monterrey, N.L., Mexico.
Metabolic syndrome (MS) has a high prevalence, with an estimated one-quarter of the world population affected by this pathological condition. Among the diseases of this syndrome are dysregulation of lipids, hypertension, and insulin resistance. Unfortunately, available drugs in the market used for treating MS, as almost 75% of all drugs, are highly insoluble, presenting a significant demand for strategies to increase their solubility.
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