Drug Metabolism and Disposition最新文献

{"title":"Advancing precision treatment in preterm infants: Population pharmacokinetics of caffeine for apnea of prematurity.","authors":"Yaodong He, Xianhuan Shen, Sengpeng Wong, Jiahao Zhu, Xixuan Wang, Qian Liu, Lian Zhang, Yiming Jiang, Wenzhou Li, Xiaomei Fan","doi":"10.1016/j.dmd.2026.100294","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100294","url":null,"abstract":"<p><p>This study aimed to develop a population pharmacokinetic (PopPK) model for caffeine in apnea of prematurity, identify clinically significant covariates that influence pharmacokinetic (PK) parameters, and establish an evidence-based, individualized dosing regimen. The observational cohort comprised 232 serum caffeine concentration measurements from 168 premature infants who received standard caffeine therapy. Data from 136 patients were used for PopPK modeling, while the remaining 32 were reserved for external validation. A 1-compartment model with first-order elimination was developed using NONMEM software. Stepwise selection was used to evaluate the influence of physiological and pathological factors, as well as concomitant medications, on PK parameters in a covariate analysis. The final model was validated using goodness-of-fit plots, bootstrap, and a prediction-corrected visual predictive check. Monte Carlo simulation was further employed to optimize dosing toward a target trough concentration of 14.5 mg/L. The final PopPK model identified current weight (CW) at sampling and sex (male infants had 20% lower clearance than female infants) as significant covariates affecting PK variability. The model was validated internally and externally. Simulations indicated that a 20 mg/kg loading dose followed by CW-stratified maintenance dosing (male infants: 7.5-10 mg/kg/day; female infants: 10-12.5 mg/kg/day across CW 750-2500 g) achieves target concentrations. We established the first PopPK model of caffeine in preterm infants, demonstrating that female sex is an independent predictor of higher clearance. The sex and CW-specific dosing algorithm supports individualized caffeine therapy, reducing apnea episodes and minimizing toxicity. SIGNIFICANCE STATEMENT: In this study, female sex was identified as a novel, independent covariate significantly associated with enhanced caffeine clearance. To translate this finding into clinical practice, we propose a practical dosing regimen to guide personalized caffeine therapy in preterm infants.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100294"},"PeriodicalIF":4.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Reaction Phenotyping and Projection of Drug Interactions Mediated by Cytochrome P450 Enzymes for Central Nervous System Drugs as Victims: Implications for Safety in Vulnerable Populations.","authors":"Veera Raghava Chowdary Palacharla, Ramakrishna Nirogi, Nitesh Kumar, Pradeep Jayarajan, Hanumanth Rao Pantangi, Surendra Petlu, Krishnadas Nandakumar","doi":"10.1016/j.dmd.2026.100295","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100295","url":null,"abstract":"<p><p>Accurate prediction of cytochrome P450-mediated victim drug-drug interactions (DDIs) is critical for the safe use of central nervous system (CNS) drugs, particularly in populations at high risk of polypharmacy. This study evaluated the utility and limitations of in vitro human liver microsomal data for predicting victim DDIs of CNS compounds metabolized by CYP1A2, CYP2B6, CYP2D6, and CYP3A4. Reaction phenotyping with isoform-selective inhibitors quantified the fractional metabolic contribution (f_m,cyp) of each enzyme, and inhibition parameters for fluvoxamine (CYP1A2), ticlopidine (CYP2B6), cinacalcet/paroxetine (CYP2D6), and ketoconazole (CYP3A4) were incorporated into a mechanistic static model using unbound hepatic inlet concentrations as surrogates for site of inhibition exposure. Predictions for CYP2B6-, CYP2D6-, and CYP3A4-mediated interactions were generally within 3-fold of observed clinical values. In contrast, CYP1A2 substrates showed high sensitivity to f_m,cyp values exceeding 0.9, resulting in underprediction (eg, ramelteon-fluvoxamine, 66-fold) or overprediction (eg, tacrine). Contributing factors may include incomplete characterization of minor metabolic pathways, hepatic accumulation of inhibitors, and limitations of static modeling assumptions. Overprediction of select CYP3A4 interactions, such as lurasidone-ketoconazole, likely reflects underestimation of the fraction escaping intestinal metabolism. These findings indicate that human liver microsome-based reaction phenotyping provides valuable guidance for early DDI risk assessment, particularly for CYP2B6, CYP2D6, and CYP3A4 substrates, but small deviations in f_m,cyp for CYP1A2 substrates can lead to substantial underestimation of clinical risk. Integration with physiologically based pharmacokinetic modeling and refined f_m,cyp estimates may enhance prediction accuracy and better inform safe CNS drug use, especially in populations prone to polypharmacy. SIGNIFICANCE STATEMENT: Accurate prediction of P450-mediated drug-drug interactions is essential for safe central nervous system drug therapy, especially in patients at high risk of polypharmacy. This study shows that human liver microsome-based reaction phenotyping reliably predicts CYP2B6, CYP2D6, and CYP3A4 interactions, whereas small deviations in f_m,cyp for CYP1A2 substrates can cause substantial under- or overprediction. Incorporating physiologically based pharmacokinetic modeling and refined f_m,cyp estimates can enhance drug-drug interaction risk assessment and guide safer coadministration of central nervous system-active drugs with potent P450 inhibitors.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100295"},"PeriodicalIF":4.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Altitude Hypoxia Dysregulates the Organic Anion Transport Network to Alter Acetazolamide Disposition and Renal Metabolic Homeostasis: Validation of the Remote Sensing and Signaling Theory.","authors":"Bohong Zheng, Mengran Wang, Jingtao Wang, Qiannan Zhang, Cong Li, Xia Wu, Wenpeng Zhang, Xiaomei Zhuang","doi":"10.1016/j.dmd.2026.100296","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100296","url":null,"abstract":"<p><p>Acute high-altitude hypoxia (AHH) disrupts systemic homeostasis and alters the pharmacokinetic (PK) profiles of drugs, yet the role of the organic anion transport network in mediating altered drug disposition and the link to regulation by the Remote Sensing and Signaling Theory remain unclear. Moreover, the underlying mechanisms governing the PK of acetazolamide (ACZ), an FDA-approved therapeutic agent for high-altitude illness, remain unelucidated. This study aimed to clarify the effects of AHH on the PK of ACZ, identify the organic anion transport network involved, and characterize perturbations in renal metabolism. Results demonstrated that AHH markedly altered ACZ PK: with a 3.27-fold increase in AUC_0-∞ and a 2.62-fold prolongation in t_1/2. For the first time, ACZ was confirmed as a specific substrate of organic anion transporter 1, multidrug resistance-related protein (MRP4), and breast cancer resistance protein. Mechanistically, AHH dysregulated these transporters, including upregulating breast cancer resistance protein, downregulating organic anion transporters, organic anion transporting polypeptides, MRPs, and P-glycoprotein via transcriptional regulation of nuclear receptors (hypoxia-inducible factor-1α, Pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor-4α), a finding validated in acute hypoxic Caco-2 cells and AHH rat models. Renal metabolomics further revealed profound perturbations in organic anion metabolism, notably, indoxyl sulfate, hippuric acid, and kynurenic acid were decreased by 56.84%, 88.53%, and 69.77%, respectively, whereas estrone glucuronide was elevated 4.78-fold, and these 4 metabolites were identified as novel renal tissue-specific biomarkers of AHH-induced renal organic anion transport network dysfunction. Collectively, this study elucidates organic anionic drug disposition mechanisms under AHH, validates Remote Sensing and Signaling Theory by linking organic anion transport network to drug metabolism crosstalk, and provides evidence for personalized pharmacotherapy of high-altitude sickness. SIGNIFICANCE STATEMENT: This study uncovers how acute high-altitude hypoxia dysregulates the organic anion transport network to disrupt acetazolamide (ACZ) disposition and renal metabolic homeostasis. It first identifies ACZ as an organic anion transporter 1/multidrug resistance-related protein 4/breast cancer resistance protein substrate and defines indoxyl sulfate, hippuric acid, kynurenic acid, and estrone glucuronide as endogenous renal tissue-specific biomarkers for organic anion transport network dysfunction. Filling the gap in understanding acute high-altitude hypoxia-mediated organic anion transport network regulation, this work validates the Remote Sensing and Signaling Theory and provides critical insights for optimizing ACZ pharmacotherapy and exploring metabolic homeostasis in high-altitude environments.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100296"},"PeriodicalIF":4.0,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MegaTrans-machine learning models for drug transporters corresponding to the FDA guidance.","authors":"Patricia A Vignaux, Melanie Tojong, Alexander Kyu, Lucy J Martinez-Guerrero, Joshua S Harris, Thomas R Lane, Stephen H Wright, Nathan J Cherrington, Sean Ekins","doi":"10.1016/j.dmd.2026.100293","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100293","url":null,"abstract":"<p><p>Regulatory guidances (eg, FDA and European Medicines Agency) require an understanding of the interactions of novel drugs, natural products, and environmental toxicants with key transporters to avoid compounds with undesirable side effects. Computational approaches to predict such interactions using machine learning models trained on in vitro data could prevent compounds that are transporter inhibitors with potential for drug-drug interactions from reaching the more costly development stages. We now describe the curation and machine learning model building for the transporters covered in the FDA guidance (organic anion transporter 1, organic anion transporter 3, organic cation transporter 2, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, P-glycoprotein, breast cancer resistance protein, multidrug and toxin extruder 1, and multidrug and toxin extruder protein 2K) that enabled the creation of MegaTrans, a web-based software product that enables users to input molecules and predict the inhibition of transporters of interest. Each dataset was used to generate machine learning models using extended-connectivity fingerprint 6 with 5-fold cross-validation. These models were also applied to a dataset (N = 39) derived from recent FDA-approved drugs and chemical property overlap with our models was determined using t-distributed stochastic neighbor embedding. In aggregate, the model predictions had an accuracy of 66%, and a second round of transporter models displayed an accuracy of 76%. Our application of literature in vitro data on transporters for building these machine learning models can be used for compound profiling, representing an approach which could minimize the need for in vitro screening experiments and help to prioritize resources. Such applications of machine learning models could also be integrated at the drug design stages in artificial intelligence approaches, including generative artificial intelligence, further broadening the impact. SIGNIFICANCE STATEMENT: MegaTrans is a computational tool to predict the inhibition of small molecules across a range of clinically relevant human drug transporters, allowing visualization of model metrics, highlighting atom-bond contributions, and visualizing chemical space overlaps between queries and model datasets.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100293"},"PeriodicalIF":4.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, expression, purification, and application of novel recombinant miR-491 molecules to define the biogenesis and function of miR-491-3p versus -5p in posttranscriptional regulation of UDP-glucuronosyltransferase 1A1.","authors":"Yimei Wang, Mei-Juan Tu, Neelu Batra, Su Guan, Yufan Zhou, Ai-Ming Yu","doi":"10.1016/j.dmd.2026.100292","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100292","url":null,"abstract":"<p><p>Interindividual variations in drug metabolism involve various factors, including posttranscriptional gene regulation mechanisms controlled by microRNAs (miRNAs or miRs) derived from the genome. The aim of this study was to use RNA bioengineering technology to produce novel recombinant human miR-491-5p, miR-491-3p, and pre-miR-491 molecules, namely BioRNA/miR-491-5p, BioRNA/miR-491-3p, and BioRNA/pre-miR-491, respectively, and define their functional difference in regulating UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and drug-metabolizing capacity. All 6 BioRNAs were heterologously overexpressed in Escherichia coli (>30% of total RNA) and isolated by fast protein liquid chromatography to high purity (>97%). As BioRNA/pre-miR-491 agents were processed to both 5p and 3p strands in Hep3B and HepG2 cells, BioRNA/miR-491-5p and -3p were selectively processed to 5p and 3p, respectively, and each accumulated to greater levels. Immunoblotting and immunofluorescence studies demonstrated the efficacy of BioRNA/miR-491-3p to suppress UGT1A1 protein levels in Hep3B and HepG2 cells, localized on the endoplasmic reticulum, exhibiting monomeric (∼55 kDa) and oligomeric (∼150 kDa) bands under different conditions, whereas BioRNA/pre-miR-491 and miR-491-5p had no effects. Using a fluorescent substrate, N-butyl-4-(4-hydroxyphenyl)-1,8-naphthalimide, lower UGT1A1 drug-metabolizing capacities were found in cells treated with BioRNA/miR-491-3p. In addition, liquid chromatography-tandem mass spectrometry analysis revealed a 45% reduction of estradiol 3-glucuronidation activity by BioRNA/miR-491-3p in Hep3B cells, whereas formation of estradiol 17-glucuronidation mediated by other UGTs was unchanged. Together, these results underline the role of miR-491-3p in regulating UGT1A1 and its impact on cellular drug-metabolizing capacity while demonstrating the applications of recombinant miRNA agents to delineating the importance of posttranscriptional gene regulation in drug metabolism. SIGNIFICANT STATEMENT: Research on posttranscriptional gene regulation mainly uses miRNA mimics chemically synthesized in vitro. This study successfully produced 6 novel recombinant miR-491 molecules through in vivo fermentation with transfer RNA scaffold and transfer RNA-fused pre-miRNA carrier-based technologies, which were further utilized to delineate the biogenesis and function of miR-491-3p versus -5p in modulating UDP-glucuronosyltransferase 1A1 protein levels and drug-metabolizing capacity. The findings demonstrate the role of miR-491-3p in regulating UDP-glucuronosyltransferase 1A1 and value of recombinant miRNA agents for studying drug metabolism.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100292"},"PeriodicalIF":4.0,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for endogenous amine conjugation and cytotoxicity arising from metabolic activation of trazodone.","authors":"Yang Wang, Yan Shen, Hao Zhou, Xialing Hao, Shibo Sun, Zixia Hu, Weiwei Li, Lixin Sun, Ying Peng, Jiang Zheng","doi":"10.1016/j.dmd.2026.100291","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100291","url":null,"abstract":"<p><p>Trazodone (TRZ), a tetracyclic antidepressant, is commonly utilized either independently or in combination with other antidepressants to treat depression. It has also been reported to be associated with multiple cases of acute liver injury, cholestasis, and jaundice, possibly due to its extensive metabolism in the liver by cytochrome P450 enzymes. Triazolopropionic aldehyde (M1) has been identified as a metabolite of TRZ. In this study, we investigated the interaction of M1 with endogenous amines and successfully detected the corresponding conjugates in rat microsomal incubation supplemented with TRZ and individual endogenous amines, including lysine, arginine, spermidine, and spermine. The corresponding conjugates were detected in cultured rat primary hepatocytes and bile samples of rats treated with TRZ. Exposure to TRZ or M1 resulted in concentration-dependent cytotoxicity in hepatocytes. Pretreatment with ketoconazole or lysine in the culture medium reduced the susceptibility of hepatocytes to the cytotoxicity of TRZ. SIGNIFICANCE STATEMENT: This study identified that triazolopropionic aldehyde, a metabolite of trazodone, can covalently bind to endogenous amines and interfere with the biosynthesis and availability of cellular glutathione. The aldehyde group is the key structural determinant of triazolopropionic aldehyde-induced cytotoxicity and plays an important role in trazodone-induced hepatocellular injury.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100291"},"PeriodicalIF":4.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative study of absorption prediction using human intestinal organoid-derived cells in static and flow conditions.","authors":"Qianying Yuan, Julie Harney, James E Finley, Xiaofeng Wu, Hannah M Moulton, Brendon Kapinos, Emi Yamaguchi, Ashley Griffith, Manthena V S Varma, Anna K Kopec, Thomas Schroeter","doi":"10.1016/j.dmd.2026.100290","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100290","url":null,"abstract":"<p><p>Reliable prediction of human oral drug absorption is critical in early-stage drug development. However, physiologically relevant intestine cell models capturing multiple drug disposition mechanisms including transport and metabolism are limited. This study assessed the potential of human intestinal organoid-derived epithelial monolayers to characterize drug permeability and absorption in 2 culture formats-a traditional static Transwell system and a dynamic fluidic gut-on-chip system. Initially, dynamic gene and protein expression profiles were characterized over 5 weeks of static culture, followed by assessments of functional permeability using control compounds. Subsequently, the effects of mechanical and chemical stimuli were explored under dynamic flow conditions. Results indicated that although the integrity of cell monolayers in static cultures remains intact for up to 5 weeks in differentiation medium, cell differentiation stages, and the expression of specific genes and proteins related to drug metabolism exhibit time-dependent variations. Fluidic cultures showed enhanced expression of drug disposition-related genes and proteins, along with relatively higher apparent permeability. Both formats demonstrated strong correlations between the measured apparent permeability and human effective permeability, and moreover, predicted fraction of drug escaping intestinal extraction well. These findings support the application of human intestinal organoid-derived intestinal epithelial models as a reliable tool to enable human absorption predictions with reduced reliance on animal models. SIGNIFICANCE STATEMENT: This study offers significant advancements in the field of oral drug absorption prediction by leveraging human intestinal organoid-derived epithelial monolayers in both static and dynamic culture systems. By demonstrating improved physiological relevance and strong correlations with human absorption parameters, the research provides a robust alternative to traditional animal and cell models. These findings support the potential application of human intestinal organoid-derived models to reduce reliance on animal testing and improve translational accuracy in early-stage drug development.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100290"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-drug interaction assessments of clinical transporter inhibition: Learnings from the Transporter Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development.","authors":"Rucha S Sane, Pallabi Mitra, Yurong Lai, Cindy Yanfei Li, Hong Shen, Kimio Tohyama, Chester Costales, Laurent Salphati, Kelly M Mahar, Daniel A J Bow, James M Vergis, Jochen Brumm, Kunal Taskar, Hugues Chanteux, Zhizhou Fang, Xiaomin Liang, Seong Hee Park, Imad Hanna, Nilay Thakkar, Xiaoyan Chu, Cornelis E C A Hop, Helen E Rollison, Mitchell E Taub, Emi Kimoto, Katherine S Fenner, Christine Xu, Kathleen M Hillgren","doi":"10.1016/j.dmd.2026.100255","DOIUrl":"10.1016/j.dmd.2026.100255","url":null,"abstract":"<p><p>The International Consortium for Innovation and Quality for Pharmaceutical Development Transporter Working Group analyzed survey results submitted by 17 member companies describing in vitro and in vivo data for drug-drug interactions (DDI) based on drug transporter inhibition. Trends for in vitro-in vivo correlation and impact of physicochemical properties on potential for clinical inhibition were explored for intestinal (P-glycoprotein/breast cancer resistance protein), hepatic (organic anion transporting polypeptide [OATP]1Bs), and renal (organic cation transporter 2/organic anion transporter/multidrug and toxin extrusion proteins) drug transporters. The dataset comprised 58 clinical inhibition studies involving 42 compounds as DDI perpetrators, balanced across Biopharmaceutics Classification System/Biopharmaceutical Drug Disposition Classification System classes and therapeutic areas. Studies were often triggered by in vitro data indicating potential clinical DDI risk or based on anticipated comedications. Overall findings suggest that the magnitude of transporter-mediated drug interactions was relatively low for the majority of the studies (<2-fold increase in exposures). Larger area under the curve, C_max, or renal clearance changes in the presence of inhibitors were often seen with compounds that inhibited more than 1 pathways. Interactions >2-fold were only reported for statin probe substrates with OATP1B, breast cancer resistance protein, and/or CYP3A4 inhibitors. Consistent with previous reports, low false negative and high false positive rates were observed when applying static cutoff criteria suggested by regulatory agencies for both P-glycoprotein and OATPs. Lastly, the physicochemical analyses demonstrated that clinical inhibitors of P-glycoprotein and breast cancer resistance protein tended to be more lipophilic than noninhibitors (median log D, 2.9 vs 1.7), and OATP1B1/1B3 inhibitors also tended to have higher molecular weights (median, 700 vs 530 Da). This work highlights current strategies for identifying transporter-mediated DDI risks and the need to incorporate additional approaches, such as biomarker profiling and predictive modeling, for nuanced insights. SIGNIFICANCE STATEMENT: A diverse dataset comprising 58 clinical studies evaluating transporter inhibition showed that inhibitors of P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptide-1B transporters tend to be more lipophilic and larger than noninhibitors. Greater than 2-fold interactions were generally observed with substrates involving multipathway inhibitors of organic anion transporting polypeptide-1B, breast cancer resistance protein, and/or CYP3A. Low false negative and high false positive rates were observed when applying the static cutoff values in the regulatory guidance, indicating adequacy of static approach with a role for additional approaches such as modeling or biomarkers for nuanced insights.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100255"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative effectiveness of 7 major human let-7-5p isoforms to modulate target gene expression in liver cells.","authors":"Joseph M Cronin, Mei-Juan Tu, Yimei Wang, Ai-Ming Yu","doi":"10.1016/j.dmd.2026.100260","DOIUrl":"10.1016/j.dmd.2026.100260","url":null,"abstract":"<p><p>Dysregulation of efflux ATP-binding cassette (ABC) transporters often confers multidrug resistance, presenting significant challenges in treating various diseases (eg, hepatocellular carcinoma [HCC]). The let-7-5p microRNAs (miRNAs), commonly downregulated in HCC, have established roles in controlling post-transcriptional gene regulation of ABC transporters (eg, multidrug resistance-associated protein 5 MRP5/ABCC5) and some oncogenes (eg, RNA-binding protein LIN28B). Although previous research has demonstrated the potential of particular let-7-5p isoforms to regulate ABC transporters and inhibit HCC cell viability, the comparative efficacy of let-7-5p isoforms whose sequences differ in several nucleosides is unknown. This study was to compare the effectiveness of 7 major let-7-5p isoforms (let-7a to let-7g) to regulate ABCC5 and LIN28B targets and inhibit HCC cell viability in vitro by using novel bioengineered RNA let-7-5p (BioRNA/let-7-5p) agents. Release of let-7-5p isoforms from individual BioRNA/let-7-5p molecules in Huh7, HepG2, and Hep3B cells was validated. Efficacy of BioRNA/let-7-5p isoforms to repress ABCC5/MRP5 and LIN28B protein levels was found to be target dependent; among them, let-7c and let-7d-5p exhibited broader regulatory efficacy against ABCC5/MRP5, while let-7d-5p emerged as the most potent suppressor of LIN28B, generally in accordance with let-7-5p abundance and target complementarity. By contrast, let-7-5p isoforms showed minimal impact on ABCC2/MRP2 and ABCC4/MRP4 protein levels. In addition, let-7-5p isoforms showed variable efficacy to inhibit the viability of different HCC cells. Together, our studies established the functional differences of let-7-5p isoforms in regulating target gene expression and inhibiting HCC cell viability, providing insights into intrinsic differences of miRNA isoforms to inform rational development of miRNA therapeutics or combination therapy. SIGNIFICANCE STATEMENT: Using novel bioengineered RNA agents, this study established the functional differences of 7 major human let-7-5p isoforms to control target gene expression and hepatocellular carcinoma cell viability in vitro. These findings demonstrate the potential of bioengineered RNA molecules to interrogate post-transcriptional gene regulation mechanisms, highlighting specific let-7-5p isoforms to modulate transporter and oncogene expression toward the development of improved therapies.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100260"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deoxynivalenol binds and impairs nuclear receptor pregnane X receptor function perturbing modulatory control over xenobiotic metabolism and disposition machinery.","authors":"Sheeba Rizvi, Priyanka Shandilya, Keshav Thakur, Neha Kumari, Rakesh K Tyagi","doi":"10.1016/j.dmd.2026.100268","DOIUrl":"10.1016/j.dmd.2026.100268","url":null,"abstract":"<p><p>Mycotoxins are prominent environmental pollutants that pose serious health risks. Deoxynivalenol (DON), a trichothecene mycotoxin, is a widespread food contaminant known to cause metabolic and hepatotoxic effects in humans and animals. Although DON-induced inflammatory responses and ribotoxic stress are well characterized, its impact on xenobiotic metabolism and disposition machinery remains unclear. The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that functions as the \"master regulator\" of detoxification and disposition machinery, including several enzymes and drug transporters. In this study, we investigated the molecular mechanism of DON-induced impairment of PXR. It is revealed that DON selectively induces nuclear translocation of PXR and its heterodimeric partner, retinoid X receptor, implying intermolecular interactions. The DON-PXR interaction appears to impair PXR transcription function, reflected in reduced transcriptional induction of key xenobiotic-metabolizing enzymes. Surprisingly, DON-induced cellular toxicity appeared to occur through generation of alternate translational isoforms of PXR. Additionally, DON disrupted receptor-chromatin interactions exhibited by PXR during mitosis. This apparently led to loss of regulatory control of PXR over the xenobiotic metabolism and disposition, thereby increasing the retention of toxicants. The findings provide the first evidence that DON acts via functional impairment of PXR, revealing a novel mechanism by which environmental mycotoxins can perturb nuclear receptor function and cellular homeostasis. SIGNIFICANT STATEMENT: The study reveals a previously unrecognized molecular mechanism by which deoxynivalenol impairs hepatic detoxification by disrupting pregnane X receptor function and chromatin interactions. Deoxynivalenol interferes as a pregnane X receptor antagonist by reducing transcription function and aberrant isoform generation, highlighting a novel pathway by which mycotoxins may influence nuclear receptor-mediated hepatic homeostasis.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100268"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}