Year: 2026
Type: editorial
Abstract: Drug metabolism and transport are fundamental determinants of the pharmacokinetics, efficacy, and safety of therapeutic agents. The processes governing absorption, distribution, metabolism, and excretion (ADME) define drug exposure at the site of action and strongly influence both therapeutic response and the occurrence of adverse effects. Over the past decades, advances in the understanding of metabolic enzymes, membrane transporters, and regulatory pathways have significantly improved the design of drugs with optimized pharmacokinetic properties and better clinical performance (1)(2)(3).The identification of key drug-metabolizing enzymes, including cytochrome P450 isoforms and conjugating enzymes, together with the characterization of uptake and efflux transporters, has provided important insights into the mechanisms controlling drug disposition. These findings have enabled the development of new therapeutic strategies, such as prodrugs designed to overcome pharmacokinetic limitations, transporter-targeted therapies, and compounds with improved tissue selectivity (4)(5)(6). At the same time, regulatory guidelines for in vitro and in vivo studies of drug metabolism and transport have evolved, facilitating a more systematic evaluation of pharmacokinetic behavior during drug development.Despite these advances, substantial challenges remain in predicting drug exposure and response in humans. Many compounds exhibit poor solubility, limited permeability, extensive metabolism, or insufficient distribution to target tissues, which may compromise their clinical efficacy. Biological barriers such as the intestinal epithelium, the blood-brain barrier, and the tumor microenvironment continue to represent significant obstacles for drug delivery (7,8). In recent years, increasing attention has been given to the role of previously underappreciated factors influencing drug metabolism and transport. Among these, the contribution of gut microbiota has emerged as an important determinant of drug biotransformation and interindividual variability in therapeutic response (9,10).Similarly, advances in nanotechnology, biomimetic delivery systems, and targeted drug carriers have opened new possibilities for improving drug stability, bioavailability, and tissue-specific distribution (4,11). Computational modeling, including physiologically based pharmacokinetic (PBPK) approaches and quantitative structure-activity relationship (QSAR) methods, has further enhanced the ability to predict drug behavior and support rational drug design (12).Modern drug development therefore requires a multidisciplinary approach that integrates experimental pharmacology, analytical chemistry, computational modeling, and clinical investigation. Combining these approaches allows for a more comprehensive understanding of drug metabolism networks and supports the development of safer and more effective therapeutic agents. Continuous progress in this field is essential for overcoming current limitations in drug delivery, reducing variability in drug response, and enabling the implementation of personalized pharmacotherapy.The studies discussed in this work reflect these ongoing efforts, covering diverse aspects of drug metabolism, pharmacokinetics, transporter function, novel drug delivery systems, and innovative therapeutic strategies. Together, they provide an overview of current directions in the field and illustrate how advances in experimental and computational methodologies contribute to the development of new drugs and to addressing future challenges in drug metabolism and transport.Recent contributions within this Research Topic further illustrate the increasing integration of advanced delivery technologies, predictive modeling, and personalized therapeutic approaches in contemporary pharmacology. Several studies emphasize the growing relevance of biomimetic and multifunctional delivery systems, including nanocarriers and extracellular vesicle-based platforms, designed to improve bioavailability, tissue selectivity, and therapeutic precision. In parallel, computational approaches such as QSAR and PBPK modeling are becoming increasingly important for the early evaluation of pharmacokinetic behavior, interaction potential, and formulation optimization. These developments reflect an ongoing transition toward more mechanistically guided and individualized therapeutic strategies while also highlighting the need for improved translational models capable of bridging experimental findings and clinical application.Recent progress in experimental pharmacology, analytical techniques, and computational modeling has significantly improved the ability to characterize drug disposition and to identify sources of variability in therapeutic response. The studies included in this section focus on pharmacokinetic characterization and the identification of factors responsible for variability in drug disposition, illustrating how classical pharmacokinetic investigations, microbiota-related research, and predictive modeling approaches together provide a more comprehensive understanding of drug metabolism and transport.A preclinical pharmacokinetic study of the novel antiepileptic candidate Q808 in rhesus monkeys demonstrated moderate oral absorption, limited absolute bioavailability, and a relatively long elimination half-life, supporting its further development. In addition, the validated LC-MS/MS method established in this study provides a useful analytical tool for future pharmacokinetic and translational investigations of Q808. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1433043/full The pharmacokinetics of complex biological compounds may differ substantially from those of small molecules. Investigation of Glycyrrhiza uralensis polysaccharides revealed biphasic elimination, wide tissue distribution, and evidence of active transport mechanisms, illustrating the challenges associated with the pharmacokinetic evaluation of macromolecular and natural products. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1431221/full Characterization of drug metabolism and transport is also essential for identifying potential drug-drug interactions and understanding the role of enzymes and transporters in drug disposition. A comprehensive metabolism and transport study of deglycosylated azithromycin, a novel transgelin agonist with positive therapeutic effects on slow transit constipation, identified multiple metabolic pathways and demonstrated that CYP3A4 is the primary enzyme involved in its biotransformation. In addition, the compound showed low intestinal permeability, was identified as a potential P-glycoprotein substrate, and exhibited inhibitory and inductive effects on several CYP isoforms, indicating a possible risk of clinically relevant drug-drug interactions.
Source: Frontiers in Pharmacology
Authors: Maja Đanić, Charles Oo, Xue Li, Momir Mikov
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7164584124