ACS Pharmacology and Translational Science最新文献

{"title":"PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors","authors":"Hyang Yeon Lee,&nbsp;Myung Ryul Lee,&nbsp;Timothy M. Fan and Paul J. Hergenrother*,&nbsp;","doi":"10.1021/acsptsci.5c0005210.1021/acsptsci.5c00052","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00052https://doi.org/10.1021/acsptsci.5c00052","url":null,"abstract":"<p >Pancreatic neuroendocrine tumors (PNETs) are rare tumors that are often diagnosed at advanced or metastatic stages, resulting in a poor prognosis. Sunitinib is an approved therapy for treatment of patients with PNETs, but low response rates and resistance have limited its impact, with autophagy and sunitinib sequestration in the lysosome identified as key resistance mechanisms. Here, we show that the combination of sunitinib with the procaspase-3 activator PAC-1 enhances PNET cell death in cell culture and in vivo in a xenograft tumor model. PAC-1 treatment enlarges lysosomes, resulting in partial lysosomal membrane permeabilization and blocking of autophagosome-lysosome fusion. These alterations lead to increased accumulation of autophagic structures, blocking autophagic flux, and a changed distribution of sunitinib from the lysosome to the cytosol. Our data show that PAC-1 modulates sunitinib-induced autophagy and blocks lysosomal trapping, potentiating sunitinib activity and increasing death of cancer cells. As both drugs are well-tolerated in patients, the data suggest evaluation of the PAC-1/sunitinib combination in a clinical trial of patients with PNET.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1140–1151 1140–1151"},"PeriodicalIF":4.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Application of Peptides Modulating the Neuropeptide Y System","authors":"Eva-Maria Jülke,&nbsp;Benginur Özbay,&nbsp;Marcin Nowicki,&nbsp;Sylvia Els-Heindl,&nbsp;Kerstin Immig,&nbsp;Karin Mörl,&nbsp;Ingo Bechmann* and Annette G. Beck-Sickinger*,&nbsp;","doi":"10.1021/acsptsci.5c0008210.1021/acsptsci.5c00082","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00082https://doi.org/10.1021/acsptsci.5c00082","url":null,"abstract":"<p >The neuropeptide Y multireceptor–multiligand system plays an important role in multiple physiological processes. Targeting the neuropeptide Y₁ (Y₁R) and Y₂ (Y₂R) receptors has gained interest in treating weight and mental disorders. Nose-to-brain delivery is an effective tool to overcome the challenges of peptide delivery to cerebral structures. In this study, fluorescently labeled peptides that selectively activate either Y₁R or Y₂R were studied. The permeability of these compounds was evaluated on Calu-3 cells, a model system of the nasal mucosa. Particular attention was paid to the stability of peptides, and translocation of the intact compounds was demonstrated by combining a permeability assay with a receptor activation assay. Two compounds, selectively targeting either Y₁R or Y₂R, were selected, and their uptake after intranasal application was analyzed <i>in vivo</i>. Two different imaging systems were compared: whole slide scanning and confocal microscopy. Both methods allow detecting specific signals from the fluorescently labeled peptides. While whole slide scanning provides a comprehensive anatomical overview, confocal microscopy offers an improved signal-to-noise ratio. Finally, peptide-specific signals were quantified over time, displaying rapid peptide uptake within the first 15 min and sustained signals for up to 24 h. Overall, cell-based and <i>in vivo</i> assays were combined to select peptides with high pharmacological potential for nasal applications.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1168–1181 1168–1181"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease","authors":"Zonghui Ma,&nbsp;Steven McAninch,&nbsp;Zhiqing Liu,&nbsp;Cun Zhang,&nbsp;Haiying Chen,&nbsp;Jing He,&nbsp;Wenjing Yang,&nbsp;Ronaldo P. Panganiban,&nbsp;Yingzi Cong,&nbsp;Gregory Yochum,&nbsp;Allan R. Brasier,&nbsp;Irina V. Pinchuk*,&nbsp;Bing Tian* and Jia Zhou*,&nbsp;","doi":"10.1021/acsptsci.5c0006810.1021/acsptsci.5c00068","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00068https://doi.org/10.1021/acsptsci.5c00068","url":null,"abstract":"<p >Inflammatory bowel disease (IBD), a chronic, progressive, and recurrent gastrointestinal inflammatory disorder, poses a significant threat to global health and exerts an adverse effect on the quality of life. Currently, there is a lack of effective therapies for IBD. Developing novel targeted therapies for IBD, particularly orally effective therapeutics, is a vital need for IBD patients. Herein, we first demonstrate that BRD4/NF-κB signaling is aberrantly activated in the colons of human IBD biopsy samples compared to that of normal healthy controls. ZL0516, a potent, selective, and orally bioavailable BRD4 BD1 inhibitor, significantly inhibits the TNFα- and LPS-induced expression of inflammatory cytokines in human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with low cytotoxicity. Intriguingly, when administered in a preventive mode, ZL0516 significantly blocks dextran sulfate sodium (DSS)-induced murine colitis. When used in a therapeutic mode, ZL0516 effectively suppresses colonic inflammation in several IBD-relevant animal models: DSS-, oxazolone (OXA)-, and flagellin (Cbir1) T cell-induced chronic murine colitis models of IBD. ZL0516 suppresses IBD inflammatory responses in vitro and in vivo by blocking the activation of the BRD4/NF-κB signaling pathway. Also, we found that RVX208, a selective BRD4 BD2 inhibitor in Phase III clinical development, only displayed marginal effects in these IBD animal models. Collectively, our results demonstrate that specific BRD4 BD1 inhibition is a novel therapeutic strategy for IBD-associated colonic inflammation, and orally effective inhibitor ZL0516 is a promising candidate for the development of a novel therapeutic regimen against IBD.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1152–1167 1152–1167"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the Mechanism of Action of the Pt(IV) Complex with Lonidamine Ligands by Ultrafast Chemical Proteomics","authors":"Ekaterina A. Imaikina,&nbsp;Ivan I. Fedorov,&nbsp;Daria D. Emekeeva,&nbsp;Elizaveta M. Kazakova,&nbsp;Leyla A. Garibova,&nbsp;Mark V. Ivanov,&nbsp;Ilya A. Shutkov,&nbsp;Alexey A. Nazarov*,&nbsp;Mikhail V. Gorshkov* and Irina A. Tarasova*,&nbsp;","doi":"10.1021/acsptsci.4c0071810.1021/acsptsci.4c00718","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00718https://doi.org/10.1021/acsptsci.4c00718","url":null,"abstract":"<p >Platinum(II) complexes such as cisplatin, among a few others, are well-known anticancer metal-based drugs approved for clinical use. In spite of their wide acceptance, the respective chemotherapy is associated with severe side effects and the ability of tumors to quickly develop resistance. To overcome these drawbacks, the novel strategy is considered, which is based on the use of platinum complexes with bioactive ligands attached to act in synergy with platinum and to further improve its pharmacological properties. Among the recently introduced multiaction prodrugs is the Pt(IV) complex with two lonidamine ligands, the latter selectively inhibiting hexokinase and, thus, glycolysis in cancer cells. While platinum-based multiaction prodrugs exhibit increased levels of activity toward cancer cells and, thus, are considered potent to overcome the resistance to cisplatin, there is a crucial need to uncover their mechanism of action by revealing all possibly affected processes and targets across the whole cellular proteome. These are challenging tasks in proteomics requiring high-throughput analysis of hundreds of samples for just a single drug-to-proteome system. In this work, we performed these analyses for 8-azaguanine and the experimental Pt(IV)-lonidamine complex applied to ovarian cancer cell line A2780 employing both mechanism- and compound-centric ultrafast chemical proteomics approaches. These approaches were based on protein expression analysis and thermal proteome profiling, respectively. Data obtained for the Pt(IV)-lonidamine complex revealed regulation of proteins involved in the glucose metabolic process associated with lonidamine, further supporting the multiaction mechanism of this prodrug action.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1106–1115 1106–1115"},"PeriodicalIF":4.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoids as Multitarget Drugs for the Treatment of Autoimmunity in Glaucoma","authors":"Lakshmi PK*,&nbsp;Rajesh Singh Pawar,&nbsp;Yogesh Kumar Katare and MS Sudheesh*,&nbsp;","doi":"10.1021/acsptsci.4c0058310.1021/acsptsci.4c00583","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00583https://doi.org/10.1021/acsptsci.4c00583","url":null,"abstract":"<p >Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system. Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut–retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity. In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"932–950 932–950"},"PeriodicalIF":4.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Erythroferrone in Anemic Rats with Chronic Kidney Disease and Chemotherapy-Induced Anemia: An Early Biomarker for Hemoglobin Response and rHuEPO Hyporesponsiveness”","authors":"Lin Zhang,&nbsp;Peng Xu and Xiaoyu Yan*,&nbsp;","doi":"10.1021/acsptsci.5c0017410.1021/acsptsci.5c00174","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00174https://doi.org/10.1021/acsptsci.5c00174","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1187 1187"},"PeriodicalIF":4.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infrared Imaging Combined with Machine Learning for Detection of the (Pre)Invasive Pancreatic Neoplasia","authors":"Danuta Liberda-Matyja,&nbsp;Kinga B. Stopa,&nbsp;Daria Krzysztofik,&nbsp;Pawel E. Ferdek*,&nbsp;Monika A. Jakubowska* and Tomasz P. Wrobel*,&nbsp;","doi":"10.1021/acsptsci.4c0068910.1021/acsptsci.4c00689","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00689https://doi.org/10.1021/acsptsci.4c00689","url":null,"abstract":"<p >With the challenge of limited early stage detection and a resulting five-year survival rate of only 13%, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Replacing the high-cost and time-consuming grading of pancreatic samples by pathologists with automated diagnostic approaches can revolutionize PDAC detection and thus accelerate patient admission into the clinical setting for treatment. To address this unmet diagnostic need and facilitate the shift of tissue screening toward automated systems, we combined stain-free histology─specifically, Fourier-transform infrared (FT-IR) imaging─with machine learning. The obtained stain-free model was trained to distinguish between normal, benign, and malignant areas in analyzed specimens using hematoxylin and eosin stained pancreatic tissues isolated from KC (Kras^G12D/+; Pdx1-Cre) or KPC mice (Kras^G12D/+; Trp53^R172H/+; Pdx1-Cre). Due to the pancreas-specific mosaic expression of the mutant <i>Kras</i> and <i>Trp53</i> genes, changes in pancreatic tissues of this mouse model of PDAC closely mirror the gradual transformation of normal pancreatic epithelia into (pre)malignant structures. Thus, this mouse model provides a reliable representation of human disease progression, which we tracked in our study with a Random Forest classifier to achieve accurate detection at the cellular level. This approach yielded a comprehensive model that distinguishes normal pancreatic tissues from pathological features such as pancreatic intraepithelial neoplasia (PanIN), cancerous regions, hemorrhages, and collagen fibers, as well as a streamlined model designed to rapidly identify normal tissues versus pathologically altered regions, including PanINs. These models offer highly accurate diagnostic tools for the early detection of pancreatic malignancies, thus significantly improving the chance for timely therapeutic intervention against PDAC.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1096–1105 1096–1105"},"PeriodicalIF":4.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00689","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spike Protein–Fibrinogen Interaction: A Novel Immune Evasion Strategy of SARS-CoV-2?","authors":"Saroj Kumar Panda,&nbsp;Shashi Singh and Parth Sarthi Sen Gupta*,&nbsp;","doi":"10.1021/acsptsci.5c0012210.1021/acsptsci.5c00122","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00122https://doi.org/10.1021/acsptsci.5c00122","url":null,"abstract":"<p >The host protein fibrinogen has been found to interact with the N-terminal domain (NTD) of the spike protein in SARS-CoV-2. However, the evolutionary benefit of this binding to the virus still remains unclear. Herein, we put forward with rationale and supporting evidence that the binding of fibrinogen to its more conserved NTD is an immune evasion strategy adopted by the virus to outsmart the NTD targeted neutralizing antibodies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1182–1184 1182–1184"},"PeriodicalIF":4.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Novel N-(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the β-Catenin Armadillo Repeats Domain as Anticancer Agent”","authors":"Marianna Nalli,&nbsp;Laura Di Magno,&nbsp;Yichao Wen,&nbsp;Xin Liu,&nbsp;Michele D’Ambrosio,&nbsp;Michela Puxeddu,&nbsp;Anastasia Parisi,&nbsp;Jessica Sebastiani,&nbsp;Andrea Sorato,&nbsp;Antonio Coluccia,&nbsp;Silvia Ripa,&nbsp;Fiorella Di Pastena,&nbsp;Davide Capelli,&nbsp;Roberta Montanari,&nbsp;Domiziana Masci,&nbsp;Andrea Urbani,&nbsp;Chiara Naro,&nbsp;Claudio Sette,&nbsp;Viviana Orlando,&nbsp;Sara D’Angelo,&nbsp;Stefano Biagioni,&nbsp;Chiara Bigogno,&nbsp;Giulio Dondio,&nbsp;Arianna Pastore,&nbsp;Mariano Stornaiuolo,&nbsp;Gianluca Canettieri*,&nbsp;Te Liu*,&nbsp;Romano Silvestri* and Giuseppe La Regina,&nbsp;","doi":"10.1021/acsptsci.5c0017510.1021/acsptsci.5c00175","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00175https://doi.org/10.1021/acsptsci.5c00175","url":null,"abstract":"","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1185–1186 1185–1186"},"PeriodicalIF":4.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing Pharmacokinetic Interactions of Tramadol, Tapentadol, and Venlafaxine: A Cutting-Edge Liquid Chromatography–Tandem Mass Spectrometry Analytical Approach in Rat Plasma","authors":"Hala M. Heneedak,&nbsp;Khaled M. Darwish,&nbsp;Samia M. Mostafa and Mohamed Saleh Elgawish*,&nbsp;","doi":"10.1021/acsptsci.4c0072210.1021/acsptsci.4c00722","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00722https://doi.org/10.1021/acsptsci.4c00722","url":null,"abstract":"<p >The detection and quantification of opioid analgesics adulterated with serotonin reuptake inhibitors are critical in forensic toxicology due to their significant clinical and legal implications. This study focuses on developing and validating a highly sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantification of tramadol (TMD), tapentadol (TAP), and venlafaxine (VEN) in small volumes of rat plasma. The method employs a straightforward single-step protein precipitation technique for sample pretreatment. Utilizing a Shim-pack Velox SP-C18 column (2.7 μm, 2.1 × 150 mm, Shimadzu, Japan), a 12 min gradient elution was performed with a mobile phase of 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Detection and quantification were achieved in multiple-reaction-monitoring mode, with ion transitions of <i>m</i>/<i>z</i> 264.3 → 58.1 for TMD, <i>m</i>/<i>z</i> 222.3 → 107.1 for TAP, <i>m</i>/<i>z</i> 278.2 → 58.2 for VEN, and <i>m</i>/<i>z</i> 195.5 → 138.1 for caffeine, which served as the internal standard (IS). The method exhibited excellent linearity, with concentration ranges of 1–500 ng/mL for TMD (<i>r</i>² = 0.9981), 1–1000 ng/mL for TAP (<i>r</i>² = 0.9972), and 1–900 ng/mL for VEN (<i>r</i>² = 0.9987) in rat plasma using only 50 μL of sample. This validated method was applied to a pharmacokinetic interaction study, revealing significant drug interactions: the maximum observed plasma concentration (<i>C</i>_max) and area under the curve (AUC) for both TMD and VEN decreased. For TMD, <i>C</i>_max decreased by 2.58-fold from 276.25 to 106.99, and AUC_0–<i>t</i> decreased by 1.4-fold from 3005.8 to 2159.3. For VEN, <i>C</i>_max decreased by 2.51-fold from 494 to 191, and AUC_0–<i>t</i> decreased by 2.3-fold from 4988 to 2114. However, for TAP, <i>C</i>_max increased by 3.4-fold from 138.54 to 471.85, and AUC_0–<i>t</i> increased by 2.66-fold from 1060.1 to 2826.8. The concurrent administration likely creates metabolic competition at CYP2D6 and UDP glycosyltransferase enzyme sites, affecting the pharmacokinetic parameters. These findings underscore the importance of further studies to monitor the simultaneous presence of these drugs and their metabolites in plasma, especially when coadministration occurs unintentionally.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 4","pages":"1116–1128 1116–1128"},"PeriodicalIF":4.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}