Drug Metabolism and Disposition最新文献

{"title":"Enantioselective determination of methylone and its major phase 1 metabolites in various biological matrices and stereochemical stability of methylone enantiomers.","authors":"Giorgia Sprega, Giorgi Kobidze, Angelo Montana, Magì Farrè, Lourdes Poyatos, Esther Papaseit, Alfredo Fabrizio Lo Faro, Giuseppe Basile, Tivadar Farkas, Francesco Paolo Busardò, Bezhan Chankvetadze","doi":"10.1016/j.dmd.2026.100332","DOIUrl":"10.1016/j.dmd.2026.100332","url":null,"abstract":"<p><p>Many publications investigate drug concentration in various matrices aiming to select the most suitable matrix for bioanalytical studies. When for chiral drugs these studies are performed using nonenantioselective analytical methods they do not provide information about ratio of enantiomers in different matrices. A previously developed enantioselective high-performance liquid chromatography-mass spectrometry method was used for the analysis of methylone and its major phase 1 metabolites in plasma, urine, oral fluid, and sweat collected from a controlled clinical study. Along with the traditional representation of results as concentration-time dependence, the ratio of enantiomers was also plotted versus time. The concentration of methylone in oral fluid was higher compared with its concentration in circulating blood. The concentration of R-(+)-methylone was higher compared with S-(-)-methylone, and the enantiomeric excess was different in different matrices. In addition, stereochemical stability of methylone was found to be matrix dependent and surprisingly less in plasma compared with that in whole blood. Because of its higher concentration and higher stability in oral fluid, methylone is detectable in this matrix over a longer period of time after its administration than in any other studied matrices. The enantiomeric ratio in oral fluid is higher compared with that in plasma. In contrast to methylone, the concentration of methylone metabolites in oral fluid, except dihydromethylone, is lower than in plasma. The correlations of methylone concentrations in different matrices are fragile, with rather high interindividual variation, and cannot serve for reliable determination of time elapsed after drug administration. SIGNIFICANCE STATEMENT: This study demonstrates that oral fluid is a superior matrix for detecting methylone due to its higher concentration and greater stereochemical stability compared with plasma and other matrices. Enantioselective analysis reveals matrix-dependent stereochemistry and highlights that metabolite patterns differ from the parent drug. These findings emphasize the importance of matrix choice and enantioselective monitoring for accurate pharmacokinetic assessment and provide critical insights for interpreting drug detection and timing in forensic and clinical settings.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100332"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337958","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":"Virtual special section: Sex and hormonal influences on drug metabolism and disposition, and related studies.","authors":"David S Riddick","doi":"10.1016/j.dmd.2026.100331","DOIUrl":"10.1016/j.dmd.2026.100331","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100331"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204207","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":"The regulatory potential of cytochrome P450-adrenodoxin interactions: Insights toward understanding redox partner regulation in drug metabolizing enzymes.","authors":"Janie E McGlohon, D Fernando Estrada","doi":"10.1016/j.dmd.2026.100338","DOIUrl":"10.1016/j.dmd.2026.100338","url":null,"abstract":"<p><p>Mitochondrial cytochrome P450 enzymes perform critical functions in steroidogenic, vitamin D, and vitamin A pathways. Their function relies on the formation of a redox complex with the soluble ferredoxin protein adrenodoxin (Adx). Mounting evidence indicates that cytochromes P450 (P450)-Adx interactions are highly context-dependent and are shaped by proximal P450 surface architecture and substrate occupancy within the active site. Although the core electron-transfer geometry is conserved across mitochondrial P450s, subtle differences at the interface and conformational adjustments allow the system to fine-tune electron delivery to support the distinct structural, mechanistic, and catalytic requirements of each enzyme. This role establishes Adx as an effector molecule in addition to an electron donor. This minireview surveys recent developments in our understanding of P450-Adx complexes, with particular attention drawn to differences in the P450 proximal surfaces. We also discuss these insights as a new framework for understanding analogous complexes in the microsomal P450s, which are important in drug metabolism. SIGNIFICANCE STATEMENT: Recent advancements in the study of P450-adrenodoxin complexes highlight the role of adrenodoxin as an effector molecule. This review seeks to contextualize these developments from the perspective of both potential therapeutics and lessons learned regarding drug metabolizing P450-redox partner protein complexes.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100338"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337984","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":"High-level expression of full-length human CYP2E1 in Escherichia coli: Comparison of full-length human CYP2E1 to truncated counterpart shows enhanced association with redox partners.","authors":"Yudong Sun, Praveen Amunugama, Yoichi Osawa, Haoming Zhang","doi":"10.1016/j.dmd.2026.100344","DOIUrl":"10.1016/j.dmd.2026.100344","url":null,"abstract":"<p><p>Few liver microsomal cytochromes P450 (P450s), especially human P450s, are recombinantly expressed in bacteria as full-length proteins. Lack of the N-terminal membrane anchor hinders studies of the interactions of microsomal P450s with redox partners. Herein, we describe the successful expression of full-length human CYP2E1, referred to as hCYP2E1FLAL, in bacteria to give a yield of ∼704 nmol/L culture. This high-level expression was achieved due to the codon optimization strategy employed to reduce free energy for translation and growth temperature. The expressed hCYP2E1FLAL was purified with a single affinity column and contained no P420, the inactive form of P450. Compared with N-terminal truncated human CYP2E1 (hCYP2E1dH), hCYP2E1FLAL exhibits elevated enzyme activity toward prototypic substrates, chlorzoxazone and p-nitrophenol, with ∼2-fold increase in k_cat in the absence of cytochrome-b₅ (cyt b₅). The elevated enzyme activity is more pronounced in the presence of cyt b₅, with a 4.3-fold increase for chlorzoxazone and a 2.5-fold increase for p-nitrophenol. Moreover, hCYP2E1FLAL binds NADPH-cytochrome P450 oxidoreductase (POR) more tightly with an apparent K_M of 0.36 ± 0.026 μM, compared to 1.2 ± 0.13 μM for truncated hCYP2E1dH. Interestingly, the presence of cyt b₅ further decreased the K_M of POR to 0.13 ± 0.014 μM for hCYP2E1FLAL as opposed to 0.40 ± 0.041 μM for hCYP2E1dH, suggesting that cyt b₅ promotes the interactions of CYP2E1 with POR. Taken together, these results suggest that the N-terminal transmembrane anchor enhances hCYP2E1-catalyzed reactions, likely by favorable interactions with POR and cyt b₅ to form active complexes with redox partners, and that the full-length enzyme is the appropriate form for further redox partner interaction studies in membrane systems. SIGNIFICANCE STATEMENT: In vitro drug metabolism by CYP2E1 is often inferred from rodent CYP2E1 or truncated human CYP2E1 due to the lack of recombinant full-length human CYP2E1. This study developed a high-level bacterial expression of full-length human CYP2E1. Comparative studies of full-length and truncated human CYP2E1 in hydroxylation of chlorzoxazone and p-nitrophenol reveal that the N-terminal anchor of human CYP2E1 is critical for promoting interactions with NADPH-cytochrome P450 oxidoreductase and cytochrome-b₅ and, hence, enzyme activity.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100344"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381834","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":"Absorption, metabolism, and excretion of single dose oral [¹⁴C]camizestrant in healthy human female participants.","authors":"Andy Sykes, Zhoupeng Zhang, Jana Skeete, Pradeep Sharma, Stephen Wilkinson, Ryan Bragg, Sasha McClain, Malin Gränfors, Isobel Leddin, Christopher Bailey, Bistra Kirova, Nand Singh, Karthick Vishwanathan, Niresh Hariparsad","doi":"10.1016/j.dmd.2026.100342","DOIUrl":"10.1016/j.dmd.2026.100342","url":null,"abstract":"<p><p>Camizestrant is a next-generation selective estrogen receptor degrader and complete estrogen receptor antagonist and is being evaluated for the treatment of patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. This phase 1, single-center, single-period, nonrandomized, open-label study sought to determine the mass balance recovery of camizestrant and conduct metabolite profiling and structural identification. Routes of elimination, safety, and tolerability were secondary objectives. Six healthy women postmenopausal participants (median age, 60.5 years, range, 59-69) were administered a single dose of 75 mg oral [¹⁴C]camizestrant (solution) following an overnight fast. Blood, urine, and fecal samples were collected at protocol-defined intervals until mass balance criteria were met. By the end of the sampling period (432 hours postdose), 82% of the administered total radioactivity was recovered in excreta (urine, 16.8%; feces, 65.2%). The amount of radioactivity excreted in the feces in the first 24 hours was minimal, providing evidence that camizestrant absorption was high; most of the administered total radioactivity in feces was recovered between 24 and 192 hours postdose, suggesting biliary elimination. Unchanged camizestrant represented 13.6% of the total drug-related material in plasma. Of the 11 identified metabolites in plasma, an N-glucuronide conjugate of camizestrant (M4) and an N-glucuronide of an acid metabolite (M14) were the most abundant (20.1% and 11.2%, respectively). Thirteen metabolites were identified in urine (M4 most abundant; 2.3% of total radioactive dose). Eight metabolites were identified in feces (oxidative defluorinated alcohol metabolite [M1] was most abundant; 14.5% of total radioactive dose); unchanged camizestrant represented 14.5% of the total radioactive dose in feces, with in vitro data supporting unchanged camizestrant being likely due, in part, to hydrolyzed M4. SIGNIFICANCE STATEMENT: This study characterizes the absorption, metabolism, and excretion of camizestrant, a next-generation selective estrogen receptor degrader and complete estrogen receptor antagonist, in healthy humans. The majority was recovered in feces between 24 and 192 hours postdose, suggesting biliary elimination of absorbed camizestrant.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100342"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396572","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":"Cytochrome P450-mediated metabolism of K31, a Ko143-derived ATP-binding cassette subfamily G member 2 inhibitor.","authors":"Fu-Ying Qin, Junjie Zhu, Bjoern Brixius, Simone Brixius-Anderko, Jiaojiao Zhang, Meera Menon, Yixian Huang, Song Li, Xiaochao Ma","doi":"10.1016/j.dmd.2026.100329","DOIUrl":"10.1016/j.dmd.2026.100329","url":null,"abstract":"<p><p>Ko143 is a potent inhibitor of ATP-binding cassette subfamily G member 2, but its development is limited by poor metabolic stability due to rapid ester hydrolysis. To address this limitation, K31, an amide analog of Ko143, was recently developed. However, the metabolic profile of K31 in human liver microsomes (HLMs) remains suboptimal, and its underlying metabolic pathways are unclear. In this study, we systematically investigated the metabolism of K31 using HLMs, recombinant cytochrome P450 (P450) enzymes, chemical inhibition assays, and metabolomic analysis. Three P450-mediated metabolites of K31 were identified, with M1 as the predominant metabolite formed via O-demethylation. P450 phenotyping revealed that CYP2J2 and CYP4F3B contribute to M1 formation, an unusual finding given their primary roles in endobiotic metabolism and the predominantly extrahepatic expression of CYP2J2. Similar CYP2J2- and CYP4F3B-mediated O-demethylation pathways were also observed for Ko143 and its analog, K2. Chemical inhibition studies in HLMs further indicated that CYP4F3B plays a more prominent role than CYP2J2 in mediating O-demethylation of all 3 compounds, suggesting that this pathway is primarily driven by CYP4F3B in the liver and by CYP2J2 in extrahepatic tissues. Collectively, these findings provide new insights into the metabolism of Ko143 derivatives and inform the rational design of next-generation ATP-binding cassette subfamily G member 2 inhibitors with improved metabolic stability, reduced off-target metabolism, and minimized drug-endobiotic interactions. SIGNIFICANCE STATEMENT: This study highlights the central role of CYP4F3B in mediating the O-demethylation of Ko143 and its analogs in the liver. This study also identified a contribution from CYP2J2, the predominant cytochrome P450 isoform in the heart, suggesting potential extrahepatic metabolism of these compounds. These findings provide a foundation for the rational design of next-generation Ko143-derived ATP-binding cassette subfamily G member 2 inhibitors with enhanced metabolic stability, reduced off-target metabolism, and minimized drug-endobiotic interactions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100329"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13380857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238965","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":"The Janus face of phase II drug-metabolizing enzymes in hypoxia: guardian of antioxidant defense or accomplice in metabolic disorders?","authors":"Yawen Xin, Qian Wang, Sencai Wang, Yae Chang, Guiqin Liu, Yabin Duan, Junbo Zhu, Xiangyang Li","doi":"10.1016/j.dmd.2026.100326","DOIUrl":"10.1016/j.dmd.2026.100326","url":null,"abstract":"<p><p>Phase II drug-metabolizing enzymes are essential for cellular detoxification and homeostasis. Their function is profoundly influenced by hypoxia; however, the specific regulatory patterns and outcomes remain elusive. This review synthesizes current evidence to reveal that hypoxia induces isoform-specific and often contradictory regulation of phase II drug-metabolizing enzymes. Such regulation creates a functional dichotomy in which these enzymes may simultaneously enhance antioxidant defenses while impairing classical detoxification pathways. We further examine the roles of cofactors, transcriptional regulation, epigenetic modifications, and the gut microbiota in mediating these hypoxia-driven responses. Furthermore, we discuss the pharmacogenomic implications of hypoxia-induced reprogramming of phase II enzymes, with the aim of informing both mechanistic research and therapeutic strategies for hypoxia-associated pathologies. SIGNIFICANCE STATEMENT: Understanding how hypoxia reprograms the activity of phase II DMEs is critical for precision medicine in hypoxic diseases. The paradoxical regulation of these enzymes-simultaneously adapting for oxidative stress while risking detoxification compromise-directly underpins variable drug responses and adverse event risks in conditions such as cancer and ischemic injury. Studying these adaptations under hypoxia may improve treatment strategies and support targeted therapies.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 7","pages":"100326"},"PeriodicalIF":3.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327597","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":"Identification of Gln422 in transmembrane domain 9 as a key amino acid residue for the selective transport of ginsenoside Re by OATP1B3","authors":"Han Liu, S Chen, Chen Zhang, Yao Dong, Lu Yang, Jiayu Jiang, Ru Huan, Chunshan Gui","doi":"10.1016/j.dmd.2026.100379","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100379","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"1 1","pages":"100379-100379"},"PeriodicalIF":0.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672148","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":"CYP3A5 polymorphism affects the disposition of tacrolimus and its metabolite in systemic circulation and peripheral tissues of mice introduced with the CYP3A5 gene.","authors":"Genki Minegishi, Yuna Hiramatsu, Manami Sugahara, Satoshi Abe, Kanako Kazuki, Atsushi Miyajima, Yasuhiro Kazuki, Kaoru Kobayashi","doi":"10.1016/j.dmd.2026.100320","DOIUrl":"10.1016/j.dmd.2026.100320","url":null,"abstract":"<p><p>The CYP3A5∗3 allele, which leads to a splicing defect resulting in the absence of the CYP3A5 protein, is the prevalent variant in most populations. Tacrolimus dose is individualized for each patient because the CYP3A5 polymorphism impacts its pharmacokinetics. Despite tacrolimus blood levels remaining within the narrow therapeutic index, some patients still experience adverse effects associated with the CYP3A5 polymorphism. Therefore, not only systemic disposition but also peripheral metabolism of tacrolimus in each tissue is considered to understand the mechanism of its adverse effects. Here, we assess the distribution of tacrolimus and its metabolite in liver, kidney, and lung using a CYP3A-humanized mouse model with CYP3A5∗1 or CYP3A5∗3. The expression of CYP3A5 and formation of desmethyl tacrolimus were found in the liver, intestine, kidney, and lung of CYP3A5∗1 mice. When the mice were orally dosed with 3 mg/kg tacrolimus, CYP3A5∗1 mice showed lower levels of tacrolimus and higher levels of desmethyl tacrolimus in their liver, kidney, and lung compared with CYP3A5∗3 mice. Furthermore, the desmethyl tacrolimus-to-tacrolimus level ratios in CYP3A5∗1 mice were higher than those in CYP3A5∗3 mice, especially in the kidney. These findings suggest that tacrolimus is metabolized in peripheral tissues expressing CYP3A5, resulting in the elevation of desmethyl tacrolimus levels in those tissues. In conclusion, we suggest the differential disposition of tacrolimus and desmethyl tacrolimus in peripheral tissues related to CYP3A5 polymorphism by using the unique mouse models carrying CYP3A5∗1 and CYP3A5∗3. SIGNIFICANCE STATEMENT: CYP3A5 was expressed in several peripheral tissues of the CYP3A5∗1 mice generated using a mammalian artificial chromosome vector. Differential disposition of tacrolimus and its metabolite was found in the tissues of CYP3A5∗1 and CYP3A5∗3 mice. This model would be a promising tool to reveal CYP3A5-mediated drug metabolism in peripheral tissues.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 6","pages":"100320"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053476","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":"Advances in organ-on-chip for drug transporter study: Key insights and hurdles.","authors":"Isy Petit, Jean-Sébastien Bernard, Quentin Faucher, Dorian Chastagner, Hélène Arnion, Florent Di Meo, Nicolas Védrenne","doi":"10.1016/j.dmd.2026.100312","DOIUrl":"10.1016/j.dmd.2026.100312","url":null,"abstract":"<p><p>Membrane transporters play a central role in the absorption, distribution, metabolism, and elimination of drugs. Beyond drug handling, these transporters regulate the transport of endogenous metabolites, contributing to physiological homeostasis. Their activity is regulated not only by intrinsic cellular mechanisms but also by signals from distant organs. Understanding these processes is crucial for accurately predicting both local and systemic pharmacokinetics, as transporter function influences drug concentrations and effects at target tissues and throughout the organism. However, most current in vitro models do not recapitulate interorgan interactions or the dynamic regulation of transporter function. Microphysiological systems, particularly organ-on-chip, offer a promising approach to studying transporter biology in a more integrated and physiologically relevant context. This review provides an overview of the development and application of organ-on-chip technologies to investigate drug transporters and their regulation. Although significant technical progress has been made, these systems often remain focused on engineering or industrial goals, with limited impact on fundamental biological questions. Moreover, the high degree of customization and widespread use of homemade organ-on-chip models, with diverse materials, geometries, and cell sources, have created substantial barriers to reproducibility and cross-laboratory comparison. We here assess the current state of the field and identify gaps in modeling transporter regulation and interorgan communication. We also explore the potential of organ-on-chip to advance our understanding of systemic pharmacology. This review aims to reposition organ-on-chip platforms not only as technological demonstrators but also as experimental systems capable of generating new biological insights into transporter function and organ crosstalk. SIGNIFICANCE STATEMENT: Membrane transporters are central regulators of drug disposition and systemic homeostasis, yet their interorgan regulation remains poorly captured by conventional models. This review highlights how organ-on-chip technologies can bridge this gap, enabling mechanistic investigation of transporter function and advancing predictive, human-relevant pharmacology.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 6","pages":"100312"},"PeriodicalIF":3.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238987","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}