Drug Metabolism and Disposition最新文献

{"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}

{"title":"P-glycoprotein-mediated impairment of doxorubicin clearance in inflammatory bowel disorders: Mechanistic insights from rat studies and whole-body physiologically based pharmacokinetic modeling.","authors":"Mo'tasem M Alsmadi","doi":"10.1016/j.dmd.2026.100254","DOIUrl":"10.1016/j.dmd.2026.100254","url":null,"abstract":"<p><p>Doxorubicin (Dox) cardiotoxicity can worsen due to increased cardiac accumulation. P-glycoprotein downregulation, common in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), may influence Dox pharmacokinetics (PK) and cardiotoxicity, but its impact remains unexplored. This study investigated the mechanistic effects of IBS/IBD on Dox-induced cardiotoxicity. An IBS/IBD rat model assessed Dox PK after intravenous bolus (2.5 mg/kg) and oral (10 mg/kg) dosing. A whole-body physiologically based pharmacokinetic model was developed to predict Dox cardiac concentration in rats and humans. In rats, intravenous Dox clearance decreased by 70% in IBS, tripling plasma concentration, while IBD had a milder effect. Oral Dox bioavailability dropped by 85% in IBS and 50% in IBD, likely due to delayed gastric emptying. The whole-body physiologically based pharmacokinetic model predicted elevated cardiac interstitial fluid (ISFHeart) Dox concentrations surpassing cardiotoxicity thresholds in IBS/IBD rats. Human simulations showed 4- to 5-fold higher plasma concentration in IBS/IBD patients receiving intravenous Dox (60 mg/m²), nearing toxic levels. IBS/IBD prolongs Dox ISFHeart retention, increasing apoptosis-mediated cardiotoxicity risk, especially with bolus dosing. These findings highlight the critical impact of IBS/IBD on Dox PK and toxicity, advocating for personalized chemotherapy approaches. SIGNIFICANCE STATEMENT: This study shows that irritable bowel syndrome and inflammatory bowel disease alter doxorubicin disposition via impaired P-glycoprotein activity, reducing clearance, elevating systemic exposure, and increasing cardiac concentration of doxorubicin. Using rat models with whole-body physiologically based pharmacokinetic simulations, this study reveals how transporter dysfunction and gastrointestinal changes influence pharmacokinetics and toxicity. Findings extend knowledge beyond dose-dependent cardiotoxicity, highlighting comorbidities in drug disposition and underscoring disease-drug interactions for precision dosing in cancer patients.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100254"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431004","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":"Lysine- and cysteine-based protein adduction resulting from metabolic activation of fraxinellone in Dictamni Cortex.","authors":"Jie Pan, Enfu Zhang, Chutian Wu, Bowen Gong, Zixia Hu, Yuan Ding, Rong Tan, Shiyu Zhang, Yufen Liao, Ting Liu, Ying Peng, Weiwei Li, Jiang Zheng","doi":"10.1016/j.dmd.2026.100259","DOIUrl":"10.1016/j.dmd.2026.100259","url":null,"abstract":"<p><p>Dictamni Cortex (DC) has been associated with herb-induced liver injury, and fraxinellone (FRA), a furan-containing constituent, is implicated as a major hepatotoxic component. However, direct evidence linking FRA bioactivation to hepatic protein adduction in vivo remains limited. Here, we synthesized pyrroline- and pyrrole-type conjugates derived from the reactive FRA-cis-enedial intermediate and established liquid chromatography-tandem mass spectrometry methods to quantify corresponding lysine and cysteine/lysine adduct markers in the mouse liver after oral dosing with FRA or DC extract. Protein adduct levels increased in a dose- and time-dependent manner, peaked at 12 hours, and remained detectable up to 120 hours. Pretreatment with the CYP3A inhibitor ketoconazole markedly reduced adduct formation, supporting a CYP3A-dependent bioactivation pathway. To enable immunochemical detection, oxidized FRA was coupled to keyhole limpet hemocyanin to generate a polyclonal antiserum that selectively recognized FRA-derived pyrroline and pyrrole motifs. Western blotting and immunofluorescence revealed increased immunoreactive bands and a pericentral (central vein > portal triad) gradient in liver lobules, with prominent nuclear staining in hepatocytes after FRA or DC extract exposure; these signals were attenuated by ketoconazole. Collectively, these data demonstrate that CYP3A-mediated formation of an electrophilic cis-enedial intermediate drives covalent modification of hepatic proteins during FRA/DC exposure. The combined liquid chromatography-tandem mass spectrometry and antibody-based assays provide complementary tools for mechanistic studies and biomarker development for furan-containing herbal constituents. SIGNIFICANCE STATEMENT: This work provides direct in vivo evidence that CYP3A-dependent bioactivation of fraxinellone generates a reactive cis-enedial that covalently modifies hepatic proteins. The liquid chromatography-tandem mass spectrometry adduct markers and a selective antiadduct antibody enable semi‑quantitative detection and spatial mapping of protein adduction, supporting mechanistic investigations and biomarker development for furan-containing herbal constituents associated with liver injury.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100259"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484496","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":"Mechanism-guided untargeted-to-targeted lipidomics identifies phosphatidylcholine 38:4 in rat bile as an Abcb4/Mdr2 inhibition marker.","authors":"Renmeng Liu, Zachary Rabow, Tingyuan Yang, Xin Yan, Yiding Hu, Chenling Xiong, Yurong Lai","doi":"10.1016/j.dmd.2026.100256","DOIUrl":"10.1016/j.dmd.2026.100256","url":null,"abstract":"<p><p>Drug-induced liver injury can occur when the canalicular phospholipid floppase multidrug resistance protein 3 (Mdr2 in rodents) is inhibited, but there is still a lack of early biomarkers to detect this risk. In this study, bile duct-cannulated rats were dosed with multidrug resistance protein 3/Mdr2 inhibitor itraconazole (ITZ; 100 mg/kg/d for 3 days) to assess phospholipid changes via an untargeted-to-targeted lipidomics workflow. Untargeted profiling of bile and liver samples identified 1347 and 2475 tentative lipids, of which 221 and 404 were phosphatidylcholines (PCs) in bile and the liver, respectively. Unsupervised principal component analysis revealed strong treatment effects on bile PCs. A volcano plot indicated a selective, but not global, reduction in biliary PCs after ITZ treatment. Among these, PC 38:4 stood out as the most consistently decreased bile species. Structural elucidation using multistage collision-induced dissociation/mass spectrometry³ fragmentations confirmed its identity as arachidonyl PC 18:0/20:4. Subsequent absolute quantitation showed that bile PC 38:4 remained stable in controls (10.5 ± 1.02 μM; 5.6% CV) but declined rapidly after the first dose of ITZ (6.89 ± 1.50 μM at 0-4 hours) and continued to decrease to 4.22 ± 0.958 μM by day 3, a 2.7-fold decrease. Conversely, hepatic PC 38:4 showed a modest, yet significant increase (∼1.2-fold). Plasma bile acids remained unaffected, supporting a mechanism involving Mdr2 rather than the bile salt export pump. These findings identify PC 38:4 (18:0/20:4) as a sensitive and mechanistically relevant marker of Mdr2 inhibition. Monitoring PC 38:4 in nonclinical species may enable early, transporter-specific drug-induced liver injury risk assessment during drug development. SIGNIFICANCE STATEMENT: Untargeted-to-targeted lipidomics workflows identified phosphatidylcholine 38:4 as a sensitive, specific, and mechanistically linked biomarker of Mdr2 inhibition in rats. Multistage collision-induced dissociation/mass spectrometry³ fragmentation further confirmed the identity as arachidonyl phosphatidylcholine 18:0/20:4. Its rapid and specific decline in the presence of the Mdr2 inhibitor itraconazole offers a potential new tool for early detection of human multidrug resistance protein 3-related liver injury risk during drug development.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100256"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484666","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":"Overestimation of the drug-drug interaction risk between remimazolam and clopidogrel.","authors":"Hisakazu Ohtani, Mao Inagaki","doi":"10.1016/j.dmd.2026.100265","DOIUrl":"10.1016/j.dmd.2026.100265","url":null,"abstract":"","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100265"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621710","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":"A semimechanistic PK/PD model-informed Taxus tablets' development: Accelerating early clinical translation of a taxane-based antitumor agent.","authors":"Yagang Li, Tianyang Jiang, Guanwen Mo, Yuzhen He, Haozheng Tang, Likun Gong, Ying Tian, Yonglong Cai, Long Wang, Xiuwen Wan, Daozheng Lin, Weichen Zhang, Yue Gao, Haitang Wen, Guoping Zhong, Jing Jin, Min Huang","doi":"10.1016/j.dmd.2026.100262","DOIUrl":"10.1016/j.dmd.2026.100262","url":null,"abstract":"<p><p>Taxus chinensis formulation is clinically utilized for the treatment of cancer, while Taxus tablet is expected to be developed as an antitumor drug for early clinical trials. Preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis could minimize ineffective exposure in antitumor clinical trials, but model-informed drug development (MIDD) is rarely used in traditional Chinese medicine. This study applied MIDD to Taxus tablets for optimal dose and schedule and set a traditional Chinese medicine MIDD example. Cytotoxicity assays, flow cytometry, and antitumor efficacy in NCI-H1975 tumor-bearing mice were conducted to generate experimental evidence and PD data, which formed the basis for PD model development. A monoclonal antibody targeting P-glycoprotein shift assays, molecular docking, and PK studies in beagle and tumor-bearing mice were performed to identify the primary PK marker and collect PK data. Additionally, PK consistency was evaluated in humanized P-glycoprotein-expressing rat models. Finally, a PK/PD model was built using concentrations in tumor tissues and simulations were for dose optimization. Taxus extracts exhibited stronger anti-proliferative activity against NCI-H1975 cells than paclitaxel (PTX) alone by inducing cell apoptosis and G2/M cell cycle arrest in NCI-H1975 cells. Taxus tablets (tumor inhibition rate: 79.3%) matched PTX injection (tumor inhibition rate: 64.0%) in efficacy with good tolerance in vivo. PK analysis confirmed PTX as the primary antitumor component of Taxus tablets compared to other taxanes, with about 10% bioavailability and a higher tumor-to-plasma exposure ratio compared with PTX injections (6.41 vs 2.95). Taxus tablet overcame approximately 73.85% P-glycoprotein barriers due to competitive inhibition from taxanes, consistent with P-glycoprotein humanized models. A semimechanistic PK/PD model was constructed using tumor PTX as the PK marker and validated by external data. Model simulations identified 4 mg/kg daily oral administration as the optimal regimen. This study confirms Taxus tablets as an effective oral antitumor agent and successfully constructs a stable PK/PD model using tumor PTX concentrations as the PK marker, which could guide optimal dose and schedule for first in human and provides a traditional Chinese medicine MIDD case. SIGNIFICANCE STATEMENT: Taxus tablets exhibit reliable antitumor efficacy with clarified dose-effect relationships, as human-consistent P-glycoprotein inhibition improved paclitaxel bioavailability and enhanced tumor/plasma exposure. In vitro and in vivo evidence supports a PK/PD model using tumor paclitaxel concentration that avoids pharmacokinetic interactions and offers a new quantitative pharmacology perspective.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100262"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572558","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":"Enzyme-substrate-inactivator complex formation can impact time-dependent inhibition kinetics.","authors":"Jaydeep Yadav, Jan Wahlstrom, Ken Korzekwa, Swati Nagar","doi":"10.1016/j.dmd.2026.100257","DOIUrl":"10.1016/j.dmd.2026.100257","url":null,"abstract":"<p><p>In order to predict drug-drug interactions (DDIs), screening and evaluating time-dependent inhibition (TDI) of cytochrome P450 is an important part of the drug discovery process. In vitro experiments are performed for obtaining TDI parameters (inhibitor binding constant, K_I, and inactivation rate constant, k_inact), which are further used for the prediction of clinical DDI. This work used numerical methods for analysis of in vitro TDI datasets to estimate K_I and k_inact. Specifically, the impact of enzyme-substrate-inhibitor (ESI) complex formation on the estimation of K_I and k_inact was evaluated. A total of 13 datasets were evaluated, all of which exhibited non-Michaelis-Menten kinetics, including activation, biphasic inactivation, partial inactivation, and multiple binding kinetics. Datasets were modeled with and without ESI formation. The difference in inactivation efficiency between models with and without ESI ranged from 0.67 to 2.94-fold across all compounds. This resulted in different DDI predictions ranging from moderate to strong DDI predictions for the same compound. These results suggest that in vitro TDI models should incorporate the observed in vitro kinetic complexities to improve confidence in in vivo DDI prediction. SIGNIFICANCE STATEMENT: In vitro time-dependent inhibition (TDI) analysis is often performed assuming that substrate kinetics do not impact the estimates of K_I and k_inact. By incorporating enzyme-substrate-inhibitor formation in the enzyme kinetic models, activation- and substrate-dependent kinetics can be modeled simultaneously with TDI, thereby providing a more accurate prediction of drug-drug interactions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100257"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572630","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":"Impact of POR and cytochrome b5 variability on the genotype-phenotype discordance of CYP2A6 and CYP2D6: A quantitative analysis in Chinese human livers.","authors":"Yan Fang, Jiyao Wang, Demeng Liu, Junle Li, Xin Tian, Na Gao, Haifeng Zhang, Qiang Wen, Hailing Qiao","doi":"10.1016/j.dmd.2026.100264","DOIUrl":"10.1016/j.dmd.2026.100264","url":null,"abstract":"<p><p>Genotyping of CYP2A6 and CYP2D6 is a cornerstone of personalized medicine; however, current dosing algorithms often assume distinct phenotypic clusters, overlooking the substantial phenotypic overlap among genotypes. This study aimed to quantify genotype-phenotype concordance and identify the mechanistic determinants of prediction discrepancies. Using 90 Chinese human liver specimens, we evaluated CYP2A6 (alleles ∗4, ∗9) and CYP2D6 (100C>T, 1661G>C, ∗2) across enzymatic activity, microsomal kinetics, and predicted in vivo hepatic clearance (CL-_H) derived via a bias-corrected in vitro-in vivo extrapolation approach. The results revealed significant phenotypic overlap, leading to poor prediction accuracy when relying solely on genotyping. For CYP2A6, the concordance rates were only 50.0%-58.3% for the ∗4 allele and 0% for the ∗9 allele at the microsomal level. Similarly, for CYP2D6, the 100TT genotype exhibited low prediction accuracy (2.4%-14.3%), and the 1661CC genotype showed a 100% discrepancy. Correlation analysis demonstrated that these discrepancies were significantly driven by variations in microsomal enzyme content and cytochrome P450 oxidoreductase activity (for CYP2A6), as well as cytochrome b5 (Cytb5) content (specifically for CYP2D6). In conclusion, genotyping alone is insufficient for precise clearance prediction. Integrating physiological covariates-specifically POR activity and Cytb5 content-into in vitro-in vivo extrapolation models is essential to resolve genotype-phenotype discordance and optimize CYP2A6- and CYP2D6-mediated drug dosing. SIGNIFICANCE STATEMENT: This study addresses a critical limitation in CYP2A6/CYP2D6 genotype-guided therapy: it quantifies their extensive phenotypic overlap (genotyping alone: 0%-58.3% reliable dosing). Its novel multilevel analysis finds cytochrome P450 oxidoreductase/Cytb5 as drivers, aiding precision dosing and genetic-only risks mitigation.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100264"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644339","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":"Pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor α activation does not affect yes-associated protein phase separation under physiological and hyperosmotic conditions.","authors":"Pengfei Zhao, Shicheng Fan, Yanying Zhou, Jianing Tian, Min Huang, Yong Lai, Zhong Zuo, Huichang Bi, Yue Gao","doi":"10.1016/j.dmd.2026.100272","DOIUrl":"10.1016/j.dmd.2026.100272","url":null,"abstract":"<p><p>Yes-associated protein (YAP) is a critical factor of the Hippo pathway, which plays a key role in regulating organ size. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor α (PPARα) are key members of the nuclear receptor superfamily, known for mediating diverse physiological and biological processes. Previous studies have demonstrated that activation of PXR, CAR, or PPARα promotes hepatomegaly and liver regeneration via YAP signaling. YAP has been reported to undergo phase separation under hyperosmotic stress, leading to enhanced expression of downstream target genes. However, it remains unknown whether PXR, CAR, or PPARα activation affects the phase separation of YAP. Therefore, this study aimed to investigate the potential effects of PXR, CAR, and PPARα activation on YAP phase separation using live-cell imaging and fluorescence recovery after photobleaching assay. The results suggested that YAP underwent phase separation under hyperosmotic stress in cells, which was associated with increased mRNA and protein expression of YAP target genes. Further live-cell imaging revealed that neither PXR, CAR, nor PPARα activation induced YAP phase separation under physiological conditions or affected its phase separation under hyperosmotic stress. In conclusion, these findings demonstrate that activation of PXR, CAR, or PPARα does not induce YAP phase separation under physiological conditions or under hyperosmotic stress. SIGNIFICANCE STATEMENT: Yes-associated protein (YAP) plays a crucial role in regulating organ size. Activation of pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor α promotes hepatomegaly and liver regeneration via YAP signaling. This study demonstrates that activation of pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor α does not induce YAP phase separation under either physiological conditions or hyperosmotic stress, which contributes to further understanding of the regulatory mechanisms involving pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor α, and YAP, providing new insights into their physiological functions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 4","pages":"100272"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653941","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":"Development of a generic physiologically based pharmacokinetic model to predict clinical pharmacokinetics and assess drug-drug interaction risks for valine-citrulline-monomethyl auristatin E-based antibody-drug conjugates.","authors":"Chaozhuang Shen, Rui Wang, Jiapin Yan, Liang Zheng, Haitang Xie, Xuehua Jiang, Ling Wang","doi":"10.1016/j.dmd.2026.100289","DOIUrl":"https://doi.org/10.1016/j.dmd.2026.100289","url":null,"abstract":"<p><p>Valine-citrulline-monomethyl auristatin E (vcMMAE)-based antibody-drug conjugates (ADCs) are potent anticancer therapeutics; however, the intricate kinetic interplay between the ADC and liberated monomethyl auristatin E (MMAE) complicates clinical safety assessments. Given that MMAE is a CYP3A4 and P-glycoprotein (P-gp) substrate/inhibitor, a mechanistic approach is essential to predict clinical pharmacokinetics (PKs) and drug-drug interaction (DDI) risks. A physiologically based PK (PBPK) model was developed by integrating the physiological parameters and drug-specific properties of the ADC, naked antibody, and MMAE. The model incorporated key disposition processes, including ADC decoupling, FcRn recycling, target-mediated drug disposition, and lysosomal MMAE release. Clinical PK data from US Food and Drug Administration-approved vcMMAE-based ADCs were used for calibration and validation. The model's utility in assessing DDI risks was evaluated by simulating coadministration with index CYP3A4 and P-gp modulators and sensitive substrates. The resulting PBPK model successfully captured the clinical PK profiles of the ADC, total antibody, and released MMAE across multiple dose levels, with most observed PK parameters falling within 2-fold of the predicted values. DDI simulations indicated that vcMMAE-based ADCs act as victims with low-to-moderate sensitivity; coadministration with ketoconazole increased MMAE exposure by 45%-85%, whereas rifampin reduced it by 49%-56%. Conversely, as perpetrators, the ADCs exhibited a negligible impact on the PK of midazolam and digoxin, suggesting a low risk of MMAE-mediated inhibition or induction of CYP3A4 and P-gp. This platform PBPK framework provides a robust mechanistic tool for evaluating ADC-related DDI risks, offering the potential to support regulatory labeling and justify clinical trial waivers. SIGNIFICANCE STATEMENT: This study establishes a mechanistic physiologically based pharmacokinetic framework integrating the complex kinetic interplay between antibody-drug conjugates and their liberated payloads. By quantitatively assessing the drug-drug interaction potential of valine-citrulline-monomethyl auristatin E-based antibody-drug conjugates as both victims and perpetrators, this work provides a scientifically justified tool to guide regulatory labeling. Importantly, this framework supports clinical drug-drug interaction trial waivers, thereby streamlining the development of next-generation targeted therapeutics.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":"54 5","pages":"100289"},"PeriodicalIF":4.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812238","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}