Drug Metabolism Research Articles (Page 1)

Due to differences in physiological characteristics and drug metabolism between children and adults, drug efficacy evaluation and safety monitoring in pediatric drug development present significant challenges. This paper proposes a data-driven incentive mechanism for pediatric drug development based on medical imaging data. This approach optimizes drug market pricing through precise imaging data, promoting accessibility and R&D efficiency for pediatric drugs. This study first collects multi-source computed tomography (CT), magnetic resonance imaging (MRI), and X-ray data, focusing on images of common pediatric diseases. After data preprocessing, a convolutional neural network (CNN) is used for feature extraction to extract key image information. Image difference methods and a U-Net image segmentation network are then used to evaluate drug efficacy and safety, quantify efficacy changes, and analyze side effects. Next, a drug efficacy-safety evaluation model is developed, and game theory is employed to design a R&D incentive mechanism. Monte Carlo simulation is combined with risk assessment to comprehensively consider factors such as cost, R&D investment, and market demand during the pricing optimization phase. A dynamic pricing strategy is implemented to ensure both economic benefits and social accessibility of the drug. Experiments have shown that the drug has a good development effect, with an average tumor volume reduction of 32.7% (95% CI: 28.4%-36.9%). The drug's impact on organ volume is within ± 2cm³, and the market pricing strategy selects a relatively optimal price point.

Drug enteric metabolism in gut microbiota-brain crosstalk.

Cryo-EM structures of human OAT1 reveal drug binding and inhibition mechanisms.

High-altitude exposure impacts hundreds of millions globally, posing a unique health challenge due to extreme stressors including hypobaric hypoxia and intense ultraviolet radiation. The gut microbiota, a microbial community residing in the intestinal tract, plays a pivotal role in maintaining host health through homeostasis. Emerging evidence highlights the gut microbiome's dual roles in facilitating host adaptation to high-altitude environments and in mediating maladaptive responses. This review explores the potential changes and mechanisms of the gut microbiota and its metabolites in mediating host adaptation and pathogenesis related to high-altitude exposure, alongside summarizing effective strategies for targeted microbiota modulation to prevent and treat altitude-related disorders. Furthermore, we discuss the influence of microbiota on drug metabolism in high-altitude populations and its potential role as diagnostic and prognostic biomarkers. Although current research remains exploratory, the gut microbiome has garnered significant interest in high-altitude medicine. With advancing investigations, microbiota-targeted interventions may emerge as critical breakthroughs for altitude disease management, paving the way for improved human adaptation to extreme environments and precision health strategies for plateau populations.

Evaluation of the intestinal absorption and hepatic metabolism is crucial to the development of orally administered drugs. Previous evaluation systems have assessed intestinal epithelial cells and hepatocytes separately. To develop an experimental system that accounts for drug transfer from the intestine to the liver, we generated a genome-edited intestine-liver-on-a-chip system (genome-edited chip) by incorporating high drug metabolism capacity genome-edited Caco-2 cells in the top channel and CYPs-UGT1A1 KI-HepG2 cells in the bottom channel of a polydimethylsiloxane-based microfluidic device. We demonstrated that the genome-edited chip enables simultaneous evaluation of drug absorption and metabolism by allowing sample collection from both the top and bottom channels. We then confirmed the feasibility of the system in experiments showing that the concentrations of CYP3A4 metabolites decreased under the influence of itraconazole or bergamottin, known CYP3A4 inhibitors. These results validate the utility of the genome-edited chip as a convenient and cost-effective tool for drug absorption and metabolism experiments that takes into account the influence of both the small intestine and liver. This system represents a significant advancement in pharmacokinetic evaluation, offering a more integrated approach to understanding drug behavior in the body. By mimicking the sequential process of intestinal absorption followed by hepatic metabolism, the genome-edited chip provides a more physiologically relevant model compared to traditional single-cell type systems.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22425-0.

BackgroundThe management of Parkinson’s disease (PD) remains challenging owing to the limitations of current therapies. Although rasagiline (RASA), a monoamine oxidase-B (MAO-B) inhibitor, offers advantages over levodopa, its efficacy as a monotherapy is moderate. Pueraria root (PR), a traditional East Asian medicine, has demonstrated neuroprotective potential against several neurodegenerative conditions. This study investigated the pharmacodynamic and pharmacokinetic interactions between RASA and PR to evaluate their potential as a combination therapy for PD.MethodsWe examined synergistic effects on MAO-B inhibition by performing MAO-B enzyme reaction assay. We measured the cell viability for evaluating the neuroprotective effects of their co-administration against 6-OHDA-induced toxicity in PC12 cells. For investigating the interaction of drug metabolism, CYP450 expressions were measured in hepatocytes using quantitative real-time polymerase chain reaction.ResultsConcentration-dependent studies revealed a significant synergistic inhibition of MAO-B activity when RASA and PR were co-administered at specific ratios, as confirmed by combination index analysis. Although neither of the two drugs alone provided significant neuroprotection at concentrations effective for MAO-B inhibition, their co-administration significantly increased the survival of in 6-OHDA-treated cells. Importantly, investigation of CYP450 metabolism demonstrated minimal interference between these compounds, with no significant alterations in the expression patterns of relevant CYP isoforms during co-administration.ConclusionThese findings suggest that the RASA – PR combination offers enhanced therapeutic potential through synergistic effects, while maintaining favourable metabolic compatibility. This study establishes a scientific foundation for integrating traditional herbal medicine with conventional pharmaceuticals in PD management, potentially allowing for reduced conventional drug dosages while improving therapeutic outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-025-05154-9.

Amiodarone is one of the most effective and commonly prescribed class III antiarrhythmic agents. However, its pharmacokinetics may be impaired and toxicity may be aggravated by metabolic disorders. The review presents data showing that dyslipidemia, obesity, and type 2 diabetes mellitus significantly affect pharmacokinetics, pharmacodynamics and toxic profile of amiodarone. These conditions alter the drug’s binding to lipoproteins, the activity of cytochrome P450- dependent monooxygenases and tissue distribution, thereby increasing the risk of accumulation and toxic effects. Chronic heart failure further impairs drug metabolism and contributes to multisystem toxicity. The current clinical guidelines do not adequately address these critical aspects. Therefore, more rigorous monitoring of these patients and their plasma drug concentration (on individual basis) is suggested, along with a generally more cautious approach to amiodarone use. Future perspectives include prospective clinical trials on amiodarone, physiologically based pharmacokinetic modeling for personalized dosing, based on body mass index, lipid profile, and comorbidities, pharmacogenomic studies (cytochrome P450 polymorphisms), as well as biomarker discovery for drug toxicity prediction.

Plasmodium vivax is the most prevalent malaria parasite in Brazil, accounting for approximately 85% of annual malaria cases. Therapeutic failure in malaria has been associated with host genetic factors that influence drug metabolism. This study aimed to evaluate the impact of Cytochrome P450 gene polymorphisms on the treatment of Plasmodium vivax malaria in Brazil. A systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. Studies were screened based on title and abstract, duplicates were removed and articles published up to August 2024 were considered. Full-text eligibility and risk of bias assessments were performed. Allelic frequencies of the identified polymorphisms were extracted from the selected studies and visualised using pie charts. Of 296 studies retrieved, eight met the inclusion criteria. Most studies focused on the association between CYP2D6 polymorphisms and malaria treatment failure, employing a genotype-based approach to predict metaboliser phenotypes. Overall, the review revealed a lack of consensus regarding the relationship between Cytochrome P450 single nucleotide polymorphisms and antimalarial drug response. The potential implications of CYP450 genetic variability for therapeutic failure and treatment safety in Brazil are discussed.

Objective: Breast Cancer (BCa) remains the leading cause of cancer-related mortality among women, underscoring the need for developing more effective novel biomarkers. This study investigated the role of Growth Arrest-Specific 2 (GAS2) and its co-expressed genes in breast cancer. Methods: RNA-Seq data from 60 matched normal and malignant breast tissue samples (GSE183947) were analyzed. Expression values were normalized using FPKM, and GAS2 co-expression networks were constructed with SUM Lasso and linear regression. Gene-gene interaction networks were examined using Gephi software. Results: GAS2 expression was significantly reduced in tumors compared with normal tissues (p < 0.01). Distinct sets of GAS2-associated genes were identified in cancer versus normal tissues, with tumor-associated partners (TAS2R14, PHF21B, CNTN5, UGT2B15) linked to drug metabolism and signaling, and normal-associated partners (DCC, STAT5A, ZCRB1) linked to transcriptional and cytoskeletal regulation. Network analysis revealed substantial differences in gene expression patterns between tumor and normal tissues, indicating GAS2’s involvement in cancer-specific signaling pathways. Conclusion: GAS2 displays context-dependent gene interactions and reduced expression in BCa, suggesting potential relevance to tumor biology. While these findings support its value as a candidate biomarker, experimental validation is required before translational applications can be established.

Parkinson disease (PD) is a complex neurodegenerative condition marked by progressive motor and nonmotor symptoms. Cytochrome P450 (P450) enzymes, notably those from the CYP1 and CYP2 families, are increasingly recognized as significant factors in the development of PD. This review examines the role of P450 enzymes in PD, covering genetic variations, copy number variations, and single nucleotide polymorphisms linked to PD pathogenicity. It also explores the regulatory mechanisms controlling P450 expression in PD and the influence of the gut microbiome and metabolites on P450 activity. Additionally, the review discusses how P450 enzymes metabolically activate drugs used to treat PD and investigates the intricate relationship between P450s and mitochondrial dysfunction. Finally, it underscores the therapeutic potential of targeting P450 enzymes for PD treatment. Understanding the diverse roles of P450 enzymes in PD may lead to innovative treatment approaches and personalized interventions for this challenging neurological disorder. SIGNIFICANCE STATEMENT: Cytochrome P450 (P450) enzymes significantly influence Parkinson disease (PD) development through their roles in drug metabolism and detoxification. Single nucleotide polymorphisms in P450 genes can alter enzyme activity, affecting PD susceptibility and progression. Gut microbiota modulates P450 function, impacting detoxification of PD-related toxins and influencing gut and blood-brain barrier integrity. Additionally, P450-mitochondrial interactions contribute to energy deficits and oxidative stress, exacerbating neurodegeneration in PD. Understanding these pathways may uncover novel therapeutic targets and personalized treatment strategies.

Transcription factors of the Nuclear Factor I (NFI) family control hepatocyte differentiation and cytochrome P450 activity in human liver

Unexpected effects of antibiotics on microbiota-mediated drug metabolism in a fistulated dog model.

Drug resistance in breast cancer: Mechanisms and strategies for management.

Mass spectrometry-based absolute quantitative proteomics of drug-metabolizing enzymes in human liver.

Harnessing large language models for structured extraction of cytochrome P450-substance interactions from biomedical texts.

Pharmacogenomics has emerged as a vital field within precision medicine and forensics, focusing on how an individual's genome affects their response to drugs. This field is essential in enhancing treatment efficacy and minimizing side effects, particularly for cancer patients with gliomas, who often face narrow therapeutic windows for anticancer agents and have a limited Food and Drug Administration-approved treatment option. Among the cytochrome P450 enzyme superfamily, CYP2B6 metabolizes drugs such as cyclophosphamide, efavirenz, methadone, and ecstasy. Genetic variation in P450 genes influences individual's drug-metabolizing capacity, making it crucial to understand CYP2B6 and its regulation to ensure the effectiveness and safety of drug therapies and determine the cause of death in drug-related cases. Previous studies have shown that activating transcription factor 5 (ATF5), a basic leucine zipper transcription factor, transactivates CYP2B6 in liver cells. Additionally, a cell-penetrating dominant-negative ATF5 (CP-DN-ATF5) peptide was developed and successfully interfered with the ATF5-mediated stabilization of antiapoptotic proteins. Our study aimed to establish the ATF5-mediated regulation of CYP2B6 in glioblastoma cells and to determine whether CP-DN-ATF5 could also promote the downregulation of CYP2B6. We used the Tat cell-penetrating peptide from HIV-1 transactivator of transcription (TAT) form, which was N-terminally fused with DN-ATF5 (TAT-CP-DN-ATF5), for our investigation. We found that ATF5 regulates CYP2B6, and the TAT-CP-DN-ATF5 peptide effectively downregulates CYP2B6 protein levels in certain glioblastoma cell lines, LN229 and GBM5. These findings suggest the potential for targeting CYP2B6 with TAT-CP-DN-ATF5 to slow drug metabolism, allowing for personalized dosing and coadministration strategies to improve treatment efficiency and reduce side effects. SIGNIFICANCE STATEMENT: The study found that the transcription factor activating transcription factor 5 regulates CYP2B6 expression in glioblastoma cell lines. Introducing a transactivator of transcription-fused cell-penetrating dominant-negative activating transcription factor 5 peptide downregulates CYP2B6 protein expression, suggesting its potential for personalized dosing strategies by targeting CYP2B6.

Comparative study of CYP450 gene regulation in human pluripotent stem cell-derived liver 2D cell and 3D organoid models.

Exploring regional variations in probiotics: Implications for efficacy and application.

Previous reports have stated that cytochrome P4502C8 (CYP2C8) catalyzes the hydroxylation of repaglinide at the 3-position of the piperidine ring, and this metabolite has been used as a marker for CYP2C8 catalytic activity in vitro and in vivo. However, data shown in the present report demonstrate unequivocally that the actual site of hydroxylation is on the adjacent 4-position. The metabolite was biosynthesized using CYP2C8, isolated, and evaluated by high resolution mass spectrometry and 1D and 2D NMR spectroscopy. Definitive assignment of the structure required 2D heteronuclear single quantum correlation NMR analysis conducted at low temperature and the data for the isolated metabolite were contrasted with data gathered for the synthetic standard of 3'-hydroxyrepaglinide diastereomers. Repaglinide 4'-hydroxylation was measured in pooled human liver microsomes and recombinant CYP2C8 with Michaelis constants of 10.2 and 5.4 μM, respectively. Because repaglinide hydroxylation is an important drug metabolism reaction that probes CYP2C8 activity, it is critical that the correct structure of the CYP2C8 generated metabolite is known. SIGNIFICANCE STATEMENT: Previous studies have misassigned the structure of the main hydroxy metabolite of repaglinide that is generated by human P4502C8 (CYP2C8). This transformation has been used as a marker for CYP2C8 in clinical and in vitro studies. These data unequivocally demonstrate that the absolute structure of the hydroxyrepaglinide metabolite generated by CYP2C8 is 4'-hydroxymetabolite, not 3'-hydroxyrepaglinide as previously claimed.

The effectiveness and tolerability of medicines can vary considerably from person to person, even at the same dose. This variation is influenced by many factors, including constitutional genetic characteristics. In fact, some people have genetic variations that are common and neutral in the population, known as polymorphisms, which can affect drug metabolism or make them more susceptible to certain adverse effects. These variations can lead to dose-dependent toxicity in the case of genetic polymorphisms of metabolic enzymes or hypersensitivity to drugs. Pharmacogenetics therefore examines the specific genetic factors of each patient to understand their sensitivity to treatment and their risk of developing side effects. By enabling proactive adjustment of dosage and/or treatment, pharmacogenetics minimizes the risk of adverse effects and offers promising prospects for a more personalized approach to tumour management. This review will focus on the potential of pharmacogenetics in cancer care, from cancer treatment to supportive care. It will provide an overview of pharmacogenetic recommendations from national and international scientific and professional societies that are currently used in clinical practice. In addition, we will discuss the challenges and perspectives associated with integrating pharmacogenetics into clinical practice for more personalized management of cancer patients.