Drug Metabolism and Disposition最新文献

{"title":"Proteomic profiling of drug and nutrient transporter expression by small intestinal region in neonates, pediatrics, and adults.","authors":"Vicky L Sun, Kai Wang, Joanne Wang, Jashvant D Unadkat, Edward J Kelly, Samuel L M Arnold","doi":"10.1016/j.dmd.2026.100398","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100398","url":null,"abstract":"<p><p>Transporters localized to the small intestinal epithelium govern the absorption of many orally administered drugs and nutrients, and thorough characterization of transporter protein abundance is key to accurate prediction of small molecule absorption. Previous studies have reported more than 100 solute carrier (SLC) and ATP-binding cassette (ABC) superfamily transporters expressed in the intestine, but only a small subset of these proteins have been quantified in native intestinal tissue. In addition, a majority of published transporter abundance data for the intestine were collected with adult tissue. Here, we report the identification and relative quantification of 87 SLC and 18 ABC superfamily transporters by intestinal region in neonatal, pediatric, and adult small intestinal mucosa using data-independent acquisition-mass spectrometry. This study identified transporters, including SLC10A2, uniquely expressed by intestinal region in all 3 age groups, and region-associated abundance for 23 SLC/ABC transporters in pediatrics and adults. The protein abundance data reported here provide a valuable resource for the prediction of nutrient and drug absorption and efflux across age and will inform future studies of specific transporters and age-associated differences in transporter abundance. SIGNIFICANCE STATEMENT: This study reported the relative abundance of key xenobiotic transporters along the length of the small intestine in neonates, pediatrics, and adults based on data-independent acquisition-mass spectrometry. Intestinal region-associated transporter protein expression was observed for drug transporters and understudied nutrient transporters across age groups.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 10","pages":"100398"},"PeriodicalIF":3.6,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105597","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":"Corrigendum to \"Profiling RNA metabolism to understand tissue and subcellular clearance of therapeutic RNA\" [Drug Metabolism and Disposition 54 (2026) 100243].","authors":"Harvey Andersen, Ryan Hill, Alec Bell, Shane Lowery, Anthony Murphy, Michael Huskin, Michael Mohutsky, Christopher M Wiethoff","doi":"10.1016/j.dmd.2026.100315","DOIUrl":"10.1016/j.dmd.2026.100315","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100315"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697317","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":"Chromobox 4 interacts with pregnane X receptor to repress CYP3A4 expression through polycomb repressive complex 1/2-mediated epigenetic regulation.","authors":"Ibuki Kamiyoshihara, Masataka Nakano, Itsuki Yokoseki, Mei Tomii, Yuichiro Higuchi, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu, Tatsuki Fukami, Miki Nakajima","doi":"10.1016/j.dmd.2026.100387","DOIUrl":"10.1016/j.dmd.2026.100387","url":null,"abstract":"<p><p>Polycomb repressive complexes (PRCs) 1 and 2 are epigenetic regulators that suppress gene transcription through histone H3 lysine K27 trimethylation. This modification, catalyzed by enhancer of zeste homolog 2 (EZH2) within PRC2, is recognized by chromobox (CBX) proteins within PRC1, leading to chromatin condensation and transcriptional repression. Although EZH2 and CBX inhibitors have been developed for cancer therapy, the role of PRC1/2 inhibition in the regulation of drug metabolism-related genes remains unclear. In this study, we investigated the regulatory mechanisms of CYP3A4 expression by PRC1/2. Treatment with GSK126, an EZH2 inhibitor, significantly increased CYP3A4 mRNA and protein levels in HepaSH cells and ShP51 cells. Among CBX family members, CBX4 knockdown increased CYP3A4 mRNA levels, whereas its overexpression suppressed them in ShP51 cells. Consistently, CBX4 knockdown enhanced rifampicin-induced CYP3A4 expression, whereas its overexpression attenuated this induction. A coimmunoprecipitation assay revealed that CBX4 interacts with pregnane X receptor (PXR) regardless of rifampicin treatment. Chromatin immunoprecipitation analysis demonstrated that both CBX4 and PXR bind to the promoter and enhancer regions of CYP3A4, and that CBX4 knockdown increases PXR binding. Formaldehyde-assisted isolation of regulatory elements assays showed that CBX4 knockdown relaxed chromatin structure at the CYP3A4 locus, which is further enhanced by rifampicin. Collectively, these findings indicate that CBX4 interacts with PXR and likely represses CYP3A4 transcription through recognition of EZH2-mediated trimethylation of lysine 27 on histone H3 and chromatin condensation, highlighting a potential risk of drug-drug interactions associated with CBX4 inhibition. SIGNIFICANCE STATEMENT: This study provides, to our knowledge, the first evidence of epigenetic mechanisms underlying CYP3A4 suppression mediated by PRC1/2. The findings demonstrate that CBX4 interacts with PXR and binds to the CYP3A4 regulatory regions, where it recognizes enhancer of zeste homolog 2-mediated trimethylation of lysine 27 on histone H3 and represses CYP3A4 transcription via chromatin condensation. Given the increasing clinical interest in CBX inhibitors for cancer therapy, these findings highlight a potential risk of drug-drug interactions associated with CBX4 inhibition.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100387"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879611","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":"Rapid and comprehensive identification of the metabolic soft spots of peptide drugs with highly cross-linked disulfide bonds by integrating established proteomic workflow with a product ion filtering strategy.","authors":"Xinyuan Ye, Huiting Qin, Wei Zhang, Chuanxiang Yao, Xinyue Zheng, Siying Zheng, Ying Xiong, Chenyue Zhu, Lili Jiang, Shuailong Jia, Hongliang Jiang, Zhifeng Du","doi":"10.1016/j.dmd.2026.100371","DOIUrl":"10.1016/j.dmd.2026.100371","url":null,"abstract":"<p><p>Disulfide bonds are conserved structural determinants in peptides, reinforcing conformational integrity and stability. Peptides constrained by disulfide bonds resist enzymatic cleavage and exhibit suppressed b/y-ion formation in bottom-up mass spectrometry. Furthermore, disulfide bond reshuffling is often overlooked by existing software, leading to incomplete metabolite identification and inaccurate mapping of metabolic soft spots. Current tools reliably identify peptides containing native or nonnative disulfide bonds, but fail to resolve peptides with highly cross-linked disulfide architectures. To address this gap, an integrated analytical strategy combining established proteomic workflow with product ion filtering was developed based on previous work. Linaclotide, insulin glargine, and insulin degludec were selected as representative peptide drugs. First, the integrated strategy's feasibility was verified using pepsin-digested linaclotide. Subsequently, the strategy was employed to map metabolic soft spots of therapeutic peptides across multiple human biological matrices. From linaclotide digests, 3 peptic fragments were confidently identified, whereas 1 in-source fragmentation artifact was excluded based on diagnostic neutral losses and retention time alignment. In human liver S9 incubation, 6 metabolites were identified with high-confidence spectral matches, and 7 metabolites were characterized in human intestinal S9 incubation, enabling unambiguous localization of linaclotide's metabolic soft spots. In addition, analysis of insulin glargine in human serum under in vitro incubation conditions identified 20 metabolites and 3 in-source fragmentation artifacts, with metabolic soft spots unambiguously assigned. Notably, 95 metabolites of insulin degludec, along with their metabolic soft spots, were mapped using the strategy, including 4 peptides containing glutamic-C16 fatty diacid that were identified by product ion filtering. SIGNIFICANCE STATEMENT: To our knowledge, this study represents the first comprehensive identification of the metabolic soft spots of linaclotide and insulin degludec across physiologically relevant enzymatic systems and biological matrices. Reduction and alkylation eliminate analytical complexity from cross-linked disulfide architectures, enabling comprehensive peptide metabolite characterization. This study provides a transferable, integrated analytical strategy for the comprehensive identification of metabolic soft spots and metabolites in other peptides with highly cross-linked disulfide bonds.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100371"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789370","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":"Cortisol drives pregnancy-associated induction of hepatic organic anion transporter 2, sodium/taurocholate cotransporting polypeptide, and organic cation transporter 1 in HepaRG cells through glucocorticoid receptor-, hepatocyte nuclear factor 1 alpha-, and hepatocyte nuclear factor 4 alpha-dependent signaling.","authors":"Sejal Sharma, Yik Pui Tsang, Jashvant D Unadkat","doi":"10.1016/j.dmd.2026.100383","DOIUrl":"10.1016/j.dmd.2026.100383","url":null,"abstract":"<p><p>Pregnancy induces or represses hepatic drug metabolism. Whether pregnancy affects hepatic drug transport is unexplored. We previously showed that a cocktail of pregnancy-related hormones induces mRNA expression and activity of sodium/taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2 (OAT2), and organic cation transporter 1 (OCT1, mRNA only) in differentiated HepaRG cells. Here, using HepaRG cells, we identified cortisol as the hormone primarily responsible for this induction and explored the underlying mechanisms. CRISPR-CRISPR-associated protein 9-mediated knockdown studies in HepaRG cells showed that the glucocorticoid receptor (GR) is the primary mediator of this response. GR knockdown markedly attenuated cortisol-induced NTCP, OAT2, and OCT1 mRNA expression and activity. Cortisol also induced the mRNA expression of regulatory factors, including pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor (HNF) 4 alpha (HNF4α). HNF4α knockdown selectively attenuated OAT2 and OCT1 induction, whereas HNF1α knockdown enhanced NTCP induction, attenuated OCT1 induction, and reduced basal organic anion transporting polypeptide 1B1 expression. In contrast, knockdown of constitutive androstane receptor or pregnane X receptor did not significantly alter cortisol-mediated transporter regulation. These data identify cortisol as the principal pregnancy-related hormone driving regulation of hepatic OAT2, NTCP, and OCT1 in HepaRG cells and indicate that this response is mediated primarily by GR, with selective downstream contributions from HNF4α and HNF1α. These findings provide mechanistic insights into pregnancy-associated changes in hepatic transporter-mediated drug disposition, including when antenatal corticosteroids are administered to pregnant women to prevent respiratory distress syndrome in their prematurely born infants. SIGNIFICANT STATEMENT: The extent and mechanisms by which pregnancy-related hormones regulate hepatic uptake transporters remain poorly defined. This study identifies cortisol as the principal pregnancy-related hormone driving sodium/taurocholate cotransporting polypeptide, organic anion transporter 2, and organic cation transporter 1 induction in HepaRG cells and shows that this response is mediated primarily through glucocorticoid receptor, with transporter-specific contributions from glucocorticoid receptor hepatocyte nuclear factor 4α and hepatocyte nuclear factor 1α.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100383"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879650","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":"Erratum to \"Physiologically based pharmacokinetic modeling of the unusual kinetics of ketoconazole due to nonlinear liver binding and metabolism in rats\" [Drug Metabolism and Disposition 54 (2026) 100355].","authors":"Hee Eun Kang, Keumhan Noh, Jianfeng Huang, Liangliang Xu, Yanfen Teng, Lilly Xu, K Sandy Pang","doi":"10.1016/j.dmd.2026.100391","DOIUrl":"10.1016/j.dmd.2026.100391","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100391"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856947","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":"Cyclosporine A, a macrocyclic peptide, is transported by organic anion transporting polypeptide 1B1/1B3 at clinically relevant doses.","authors":"Sumathy Mathialagan, Sook Wah Yee, Christine C Orozco, Steven Scott Gernhardt, Emi Yamaguchi, Mark A West, Sara Sannino, Tracy Brown Phillips, Ruth F Sommese, David A Tess, Manthena V S Varma","doi":"10.1016/j.dmd.2026.100381","DOIUrl":"10.1016/j.dmd.2026.100381","url":null,"abstract":"<p><p>Cyclosporine A (CSA) is a large lipophilic cyclic peptide used primarily for the prevention of organ rejection following transplantation. Because of the narrow therapeutic window and variable pharmacokinetics, therapeutic drug monitoring is considered in CSA dosing. Hepatic and intestinal CYP3A-mediated metabolism is known to determine CSA pharmacokinetics and drug-drug interactions; however, the mechanisms governing its entry into hepatocytes are not well understood. Here, we evaluated the hepatic uptake mechanism(s) of CSA using transporter-transfected cell systems and Oatp1a/1b knockout mice. [³H]-CSA exhibited robust organic anion transporting polypeptide (OATP)1B1/1B3-mediated transport, with uptake ratios of up to 4-fold at 10 and 50 nM. OATP1B1/1B3-specific transport was diminished at higher CSA concentrations and in the presence of excess unlabeled (\"cold\") CSA or the OATP1B inhibitor, rifamycin SV. No transport was apparent via other major hepatic uptake transporters, including Na⁺-taurocholate cotransporting polypeptide. Intravenous clearance was ∼2.4-fold lower (P < .05) in the Oatp1a/1b knockout mice compared with wild-type mice. Additional transport studies in OATP1B-transfected cells revealed an efflux half-life of up to 110 minutes, suggesting prolonged cell retention. A 30-minute preincubation produced a 3- to 9-fold shift (potentiation) in cold CSA OATP1B IC₅₀ values when using [³H]-CSA as probe substrate. In conclusion, to our knowledge, these studies demonstrate for the first time a specific transport mechanism for cyclosporine uptake in the human liver and suggest that OATP1B1/1B3 has a critical role in its pharmacokinetics. Low uptake and efflux rates may suggest slower dissociation of CSA from OATP1B, leading to the apparent time-dependent inhibition effect in spite of the competitive interaction mechanism. SIGNIFICANCE STATEMENT: The in vitro and in vivo results of this study suggest that organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake plays a significant role in the pharmacokinetics of cyclosporine. Considerations of drug-induced or genotypic modulations in OATP1B activity are, therefore, important in optimizing dosing for this narrow therapeutic index drug. This serves as an example of a macrocyclic peptide involving OATP1B substrate activity at clinically relevant concentrations.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100381"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856938","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":"Persistent activation of growth hormone contributes to sexual dimorphic expression of hepatic drug metabolizing enzymes in Fgf15 transgenic mice.","authors":"Manyun Dai, Hong Shi, Veronia Basaly, Vik Meadows, Bo Kong, Grace L Guo","doi":"10.1016/j.dmd.2026.100368","DOIUrl":"10.1016/j.dmd.2026.100368","url":null,"abstract":"<p><p>Hepatic sexual dimorphism is critical for maintaining sex-specific metabolic pathways and xenobiotic clearance. We have demonstrated that in fibroblast growth factor 15 (Fgf15) transgenic (Tg) mice, FGF15 overexpression significantly reduced bile acid (BA) levels and induced hepatic feminization in males, marked by a male-to-female shift in expression of the drug metabolizing enzymes. This feminization is linked to the disruption of pulsatile growth hormone (GH) secretion pattern and signaling. However, it remained unclear whether FGF15 overexpression broadly disrupts hepatic sexual dimorphism or specifically drives a directional feminization program independent of biological sex. In this study, we profiled the hepatic transcriptome of female Fgf15 Tg mice and replenished male Fgf15 Tg mice with exogenous, pulsatile GH to test to what degree changes in the GH axis maintain liver dimorphism under low BA conditions. Beyond suppressing BA synthesis and altering steroid metabolism, female Tg mice altered expression of genes in xenobiotic metabolism and detoxification pathways, suggesting that the FGF15/BA axis regulates xenobiotic processing in females as well. Notably, FGF15 overexpression further amplified the baseline female expression profile of drug-metabolizing enzymes, characterized by the upregulation of female-predominant genes (Cyp2b9, Cyp3a41, Sult1e1, and Ugt1a1) and the suppression of male-predominant genes (Cyp7b1, Cyp2d9, Hsd3b5, and Igf1). Furthermore, pulsatile GH replenishment in male Tg mice partially restored male-predominant gene expression patterns. Taken together, these findings demonstrate that overexpression of intestine-derived FGF15 drives the feminization of sexually dimorphic hepatic gene expression independent of biological sex, a process that is at least partially mediated by impaired GH signaling. SIGNIFICANCE STATEMENT: Fibroblast growth factor 15 (Fgf15) overexpression intensified hepatic feminization of drug-metabolizing enzyme expression in female Fgf15 transgenic mice, similar to male Fgf15 transgenic mice. Restoring growth hormone signaling partially rescued the male-predominant gene expression pattern in male Fgf15 transgenic mice. This indicates that disruptions to growth hormone pulsatility, alongside sustained hepatic signal transducer and activator of transcription 5 activation, contribute to FGF15-induced hepatic gene feminization.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100368"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758979","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":"Endogenous biomarkers for assessing CYP3A4 and CYP2D6 activity: A critical review.","authors":"Shambhavi Parab, Imam H Shaik, Raman Venkataramanan","doi":"10.1016/j.dmd.2026.100374","DOIUrl":"10.1016/j.dmd.2026.100374","url":null,"abstract":"<p><p>Cytochrome P450 (P450) enzymes play an important role in the biotransformation of both exogenous and endogenous compounds. Variability in P450 expression and activity impacts drug-metabolizing capacity and contributes to interindividual differences in drug exposure and therapeutic outcomes. Exogenous probe substrates have traditionally been used to assess the in vivo P450 enzyme activity. However, their application can be limited in vulnerable populations such as pregnancy, transplantation, pediatrics, and elderly. Endogenous biomarkers have emerged as minimally invasive potential alternatives that can reflect the P450 enzyme activity under different physiologic and clinical conditions. In this minireview, we critically examine various endogenous biomarkers that have been proposed to assess P450 activity, with specific emphasis on CYP3A4 and also discuss emerging endogenous biomarkers of CYP2D6 activity. We summarize mechanistic and translational applicability and regulatory guidelines in predicting drug-drug interactions and use of mathematical modeling and simulation approaches to validate the biomarkers. Additionally, we discuss the potential role of metabolomics in endogenous biomarker discovery and outline current limitations and future directions underscoring the utility of endogenous biomarkers in drug metabolism and drug disposition in patients. SIGNIFICANCE STATEMENT: Endogenous biomarkers offer a minimally invasive mechanistic approach for assessing in vivo P450 activity and complement traditional drug probe-based phenotyping strategies. This minireview evaluates the currently used endogenous biomarkers of CYP3A4 and emerging candidates for CYP2D6, highlighting their translational advances, limitations, and potential integration with metabolomics and model-informed drug development for drug disposition and interaction assessment.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100374"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850013","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":"Current evidence supporting solanidine and its metabolites as biomarkers of CYP2D6 activity.","authors":"Deborah Montmeat, Anne-Priscille Trouvin, Clément Delage, Didier Borderie, Matthieu Lilamand, Xavier Declèves, Théodore Decaix","doi":"10.1016/j.dmd.2026.100382","DOIUrl":"10.1016/j.dmd.2026.100382","url":null,"abstract":"<p><p>CYP2D6 is a key determinant of drug metabolism and interindividual variability in drug response. Although genotyping is increasingly used in clinical practice, it cannot fully capture in vivo enzyme activity, which is strongly influenced by environmental and clinical factors causing phenoconversion. This limitation highlights the need for noninvasive biomarkers that provide a functional, real-time assessment of CYP2D6 activity. Over the past decade, solanidine-a potato-derived steroidal alkaloid-and its CYP2D6-dependent metabolites, especially 4-hydroxysolanidine and 3,4-seco-solanidine-3,4-dioic acid, have emerged as promising candidates. Initially identified through untargeted metabolomics, these compounds consistently reflect CYP2D6 activity across diverse populations and analytical methods. Poor metabolizers exhibit marked accumulation of solanidine and near absence of its metabolites. These biomarkers are sensitive to pharmacological CYP2D6 inhibition and correlate with established probe drugs, capturing both genetic and environmental determinants of enzyme activity, including phenoconversion and rare variants missed by genotyping. Despite challenges related to dietary exposure and analytical standardization, current evidence supports solanidine and its metabolites as practical, noninvasive biomarkers that complement pharmacogenetic testing in precision medicine. This minireview synthesizes the current evidence on their identification, functional relevance, and emerging applications in CYP2D6 phenotyping. SIGNIFICANCE STATEMENT: Solanidine and its CYP2D6-dependent metabolites emerge as promising noninvasive biomarkers of CYP2D6 activity, enabling real-time functional phenotyping beyond genotype alone. They reliably identify poor metabolizers and detect phenoconversion in complex clinical settings, offering a practical complement to pharmacogenetics and advancing precision dosing in populations where traditional phenotyping is impractical. However, current evidence suggests limited discrimination between adjacent phenotype groups, particularly intermediate, normal, and ultrarapid metabolizers, highlighting the need for further validation studies.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 9","pages":"100382"},"PeriodicalIF":3.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850071","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}