Pharmacological Reports最新文献

{"title":"The effect of salidroside, an active component of Rhodiola rosea, on the metabolic activity of rat and human cytochromes P450 in preclinical studies.","authors":"Eva Klaskova, Jan Jurica, Przemysław Jan Danek, Natalie Mlcuchova, Saltuk Mustafa Eyrilmez, Petra Borilova Linhartova, David Bednar, Rajamanikkam Kamaraj, Władysława Anna Daniel, Ondrej Zendulka","doi":"10.1007/s43440-026-00842-w","DOIUrl":"10.1007/s43440-026-00842-w","url":null,"abstract":"<p><p>BACKGROUND: Salidroside (SAL) is the active ingredient of the traditional adaptogenic herb Rhodiola rosea. Cytochromes P450 (P450), crucial enzymes in drug metabolism, are central to understanding drug–herb interactions. This study investigates the impact of SAL on the metabolic activity of selected P450 in both rat and human systems. METHODS: Wistar rats were administered intragastrically with SAL 5, 15, or 45 mg/kg/day for seven days. The metabolic activity of CYP1A2, CYP2C6, CYP2D, and CYP3A was measured in rat liver microsomes (RLMs). Amounts and gene expressions of CYP1A2 and CYP2C6 were assessed in RLMs using Western blot and two-step qRT-PCR. rPXR, hPXR, and CAR3 gene reporter assays were conducted. The in vitro inhibitory studies of SAL in both drug-naïve rat and human liver microsomes were performed. Interactions between SAL and human P450 were also studied by in silico methods. RESULTS: SAL at the dose of 5 mg/kg/day slightly increased the specific activity of the P450 studied. However, SAL did not change either the P450 protein levels or the expression of the corresponding genes in rat liver. It also did not cause direct inhibition of rat and human P450 in liver microsomes in vitro. Molecular docking with human P450 confirmed these findings. Moreover, SAL inhibited the agonist-mediated induction of both rat and human PXR. CONCLUSIONS: Based on our findings, SAL is unlikely to pose a significant risk of P450-mediated drug-herb interactions and rather preserves the constitutional CYP3A metabolic activity via interaction with PXR. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"808-825"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434115","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":"Prospects and challenges in intracellular delivery of therapeutic proteins.","authors":"Zakia Sultana, Ashif Ahamed, Muddasarul Hoda, Safdar Ali, Mehboob Hoque","doi":"10.1007/s43440-026-00855-5","DOIUrl":"10.1007/s43440-026-00855-5","url":null,"abstract":"<p><p>Small-molecule drugs have gained significant interest in therapeutic development. However, their therapeutic efficacy is often limited by poor target specificity, low bioavailability, and increased toxicity at higher doses. In recent years, biomolecule-based therapeutics such as proteins and peptides have emerged as promising alternatives due to their high specificity, solubility, and low toxicity. Despite these advantages, the intracellular delivery of these molecules remains challenging due to their poor stability, short half-life, and endo-lysosomal entrapment. Several delivery strategies have been developed to overcome these limitations, such as chemical modifications, structural modifications like poly(ethylene glycol) conjugation (PEGylation), and advanced carrier systems such as cell-penetrating peptides (CPPs), nanoparticles (NPs), functional polymers, and antibody-based delivery systems. Non-viral delivery systems have gained considerable attention due to their biocompatibility, low toxicity, and relatively high efficiency. This review provides a comprehensive overview of the various intracellular delivery strategies of therapeutic proteins, highlighting their mechanisms of cellular uptake, advantages, limitations, and future perspectives in biomedical applications.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"679-706"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841345","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":"Isoxazole derivatives as multi-target agents: virucidal, antibacterial, and antiproliferative effects on skin cancer cells.","authors":"Izabela Jęśkowiak-Kossakowska, Paulina Nowotarska, Elżbieta Gębarowska, Barbara Bażanów, Tomasz Gębarowski, Roman Szafran, Aleksandra Chwirot, Edward Krzyżak, Adam Szeląg, Marcin Mączyński, Maciej Janeczek, Benita Wiatrak","doi":"10.1007/s43440-026-00839-5","DOIUrl":"10.1007/s43440-026-00839-5","url":null,"abstract":"<p><strong>Background: </strong>The convergence of microbial infections and cancer risk in inflammatory skin diseases demands novel, multi-functional therapeutics. This challenge is exacerbated by the rise in antimicrobial resistance and the lack of approved drugs for pathogens like human adenovirus (HAdV).</p><p><strong>Methods: </strong>Here, we investigated a series of isoxazole derivatives to identify lead candidates with combined antibacterial, antiviral, and anticancer properties for dermatological applications. The tests performed include antibacterial agar diffusion assay, antiviral quantitative suspension test, in silico and in vitro assays such as MTT, Rho-123, DCF-DA, Griess, as well as ELISA tests (Caspase-3, IL-6, TNF-α, COX), and detection of apoptosis in a microchip.</p><p><strong>Results: </strong>Our study identified compound MO3 with significant antibacterial action against Staphylococcus aureus and the zoonotic pathogen Staphylococcus pseudintermedius. In antiviral assays, MO10 and MO7 demonstrated exceptionally high virucidal potency against HSV-1 (100-fold greater than the threshold) and AdV-5 (10-fold greater than the threshold), respectively, while remaining non-toxic to human fibroblasts. Critically, MO10 also exhibited multi-modal anticancer effects in melanoma, inducing NO-mediated apoptosis, reducing pro-inflammatory cytokines, and acting in strong synergy with doxorubicin to enhance its chemotherapeutic effect.</p><p><strong>Conclusion: </strong>In conclusion, this work validates specific isoxazole derivatives as highly promising candidates for development: MO3 for resistant bacterial infections, MO7 for otherwise untreatable adenovirus infections, and MO10 as a dual-action agent against HSV-1 and an adjunct to melanoma chemotherapy.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"775-794"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355801","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":"Trimetazidine modulates angiogenesis, inflammation, and metabolism-related gene expression to promote diabetic foot ulcer healing: a transcriptomic analysis.","authors":"Dorian Dulcic, Lucija Dumancic, Andrea Crkvenac Gregorek, Majda Vrkic Kirhmajer, Robert Likic","doi":"10.1007/s43440-026-00841-x","DOIUrl":"10.1007/s43440-026-00841-x","url":null,"abstract":"<p><strong>Background: </strong>Diabetic foot ulcers (DFUs) are a chronic complication of diabetes associated with impaired healing and tissue ischemia.</p><p><strong>Aim: </strong>This study explores the transcriptional effects of trimetazidine (TMZ) in wound-relevant human cell models to generate hypotheses regarding its potential mechanisms of action.</p><p><strong>Methods: </strong>We conducted a secondary analysis of LINCS Phase 5 transcriptomic data to evaluate TMZ-induced gene expression in four human cell lines relevant to DFU pathophysiology: HUVEC (endothelial), THP1 (monocytic), A375 (keratinocytic-like), and MCF7 (epithelial-like).</p><p><strong>Results: </strong>TMZ induced 700-900 differentially expressed genes per cell line, with distinct yet convergent responses across models. A consistent activation of the PI3K-Akt signaling pathway was observed, along with modulation of noncanonical NF-κB components such as RELB and CXCL2. TMZ promoted metabolic reprogramming, including SIRT3 upregulation and glycolysis inhibition, and selectively regulated extracellular matrix remodeling genes. Importantly, pro-angiogenic and anti-inflammatory signatures emerged independently of VEGF, with notable downregulation of PTGS2 and TLR4.</p><p><strong>Conclusion: </strong>These results highlight TMZ's potential to modulate gene networks associated with angiogenesis, inflammation, and metabolism. The findings are exploratory and warrant validation in preclinical models to assess their therapeutic relevance.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"795-807"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207225","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":"Ketamine for comorbid treatment-resistant depression and substance use disorders: balancing risks and opportunities.","authors":"Benjamin D Brody, Dora Kanellopoulos","doi":"10.1007/s43440-026-00843-9","DOIUrl":"10.1007/s43440-026-00843-9","url":null,"abstract":"<p><p>Recent retrospective analyses have shown that individuals with comorbid Substance Use Disorders (SUDs) are overrepresented among responders to ketamine for Treatment Resistant Depression (TRD). Ketamine is an effective treatment for depression and also a potential substance of misuse. The authors contrast a mechanistic pathway with a possible expectancy effect to account for these findings, and urge careful consideration of risks and benefits when considering ketamine for individuals with TRD and SUDs.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"625-626"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434100","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":"New molecules candidates with a semicarbazide scaffold - anticancer potential in view of research on their physicochemical properties, antioxidant activity, and preliminary biological activity.","authors":"Łucja Justyna Walczak, Marta Arczewska, Zbigniew Karczmarzyk, Monika Gawrońska-Grzywacz, Agnieszka Wieleba, Daniel Kamiński, Monika Pitucha, Waldemar Wysocki, Mariola Herbet","doi":"10.1007/s43440-026-00844-8","DOIUrl":"10.1007/s43440-026-00844-8","url":null,"abstract":"<p><p>BACKGROUND: Developing semicarbazide-based compounds as potential therapeutic agents is a promising direction in medicinal chemistry, particularly in the context of anticancer drug design. This study reports the synthesis and comprehensive physicochemical characterisation of a series of novel semicarbazide derivatives (AW8, AW12, AW19, AW23, AW33, AW38). METHODS: Molecular structures and tautomeric forms in the crystalline state were elucidated using single-crystal X-ray diffraction and supported by detailed Fourier Transform Infrared Spectroscopy (FT-IR) analysis. Incorporation into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based model lipid membranes was evaluated using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Langmuir monolayer techniques. Theoretical absorption, distribution, metabolism, and excretion (ADME) properties and in silico predictions were generated using SwissADME and ADMETlab 3.0 software platforms. Antioxidant potential was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, and cytotoxicity against PANC-1 pancreatic cancer cells was determined using the 3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The compounds exhibited distinct hydrogen-bonding patterns, conformational preferences driven by substituent-dependent electronic effects, and characteristic supramolecular interactions governing their crystal packing, as confirmed by Hirshfeld surface analysis. Among the tested derivatives, AW8 and AW12 demonstrated the highest membrane affinity, inducing significant spectral alterations and surface pressure changes, indicative of enhanced membrane perturbation associated with chlorine substitution. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions revealed favourable pharmacokinetic profiles, including the potential for blood–brain barrier penetration in selected derivatives and predicted inhibition of P-glycoprotein, a key mediator of multidrug resistance. The compounds demonstrated moderate radical scavenging activity and dose-dependent cytotoxicity against PANC-1 cells. CONCLUSION: These findings indicate that the studied semicarbazides exhibit promising membrane-active properties, favourable ADME profiles, and biological activity relevant to anticancer drug development, supporting their further evaluation as potential therapeutic candidates. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"826-848"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355750","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":"Achieving target plasma concentrations of beta-lactam antibiotics in critically ill patients: a retrospective study of full-dose administration in the first 24 hours.","authors":"Milada Halačová, Marie Mieresová, Jan Kubele, Eva Klapková, Dalibor Černý, Petr Waldauf, František Duška","doi":"10.1007/s43440-026-00836-8","DOIUrl":"10.1007/s43440-026-00836-8","url":null,"abstract":"<p><p>BACKGROUND: Beta-lactams are the cornerstone of therapy for the treatment of the most serious infections in the intensive care unit (ICU) setting. However, individualization of dosing remains challenging because pharmacokinetics are highly variable and difficult to predict in critically ill patients. The objective of this study was to evaluate whether administration of full-dose beta-lactam antibiotics to critically ill subjects during the first 24 h of treatment, irrespective of baseline renal function, achieves predefined target concentration ranges (Cmin [free minimum concentration] 1–10 × MIC [minimum inhibitory concentration] and 4–10 × MIC). METHODS: This trial was a retrospective, observational cohort study. A total of 377 critically ill patients over 18 years admitted to the ICU who received full doses of meropenem, piperacillin–tazobactam, or cefepime were analyzed. Blood sampling for determination of antibiotic trough concentration was performed 24 h after initiation of full-dose therapy. RESULTS: When targeting a Cmin of 4–10 × MIC, a high proportion of patients remained underdosed (42.7%, N = 161). In contrast, when targeting a Cmin of 1–10 × MIC, only 13.3% (N = 50) of patients failed to reach the target range. Seventy-four patients (19.6%) were found to be above the defined target range (Cmin > 10 × MIC). Reduced glomerular filtration rate (GFR) was a consistent independent predictor of achieved plasma level across the overall population, as well as within individual subsets. No adverse effects (neurotoxicity, hematotoxicity, hepatotoxicity) were observed. CONCLUSIONS: With full-dose beta-lactam administration, targeting a Cmin of 4–10 × MIC results in a high proportion of patients being underdosed, whereas a target of 1–10 × MIC is achieved in the majority of patients. Our results highlight the importance of therapeutic drug monitoring (TDM) of beta-lactam antibiotics in critically ill patients. Further research in this field is warranted. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"929-944"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147284305","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":"Propafenone-mediated gap junctional uncoupling results from aberrant connexin-43 trafficking.","authors":"Encan Li, Najla Boujeddaine, Britt Mol, Emmy Penning de Vries, Marcel A G van der Heyden","doi":"10.1007/s43440-026-00845-7","DOIUrl":"10.1007/s43440-026-00845-7","url":null,"abstract":"<p><p>BACKGROUND: Connexin-43 (Cx43) is the principal gap junction protein in the heart, mediating electrical coupling and ion exchange between cardiomyocytes to maintain synchronous contraction. Any disruption or malfunction of Cx43 can lead to arrhythmias and other cardiac issues. Understanding the functions and regulation of Cx43 is vital in both basic research and clinical contexts. Propafenone, a class Ic antiarrhythmic drug, has shown promise in rhythm control; however, its precise impact on cardiac cellular physiology, particularly regarding Cx43, remains incompletely understood. The present study investigated propafenone’s effects on Cx43 protein content, physiology, and underlying mechanisms in cell systems. METHODS: Cell lines include human embryonic kidney HEK293 cells transfected with Cx43 (Ex-HEK); differentiated murine embryonic carcinoma EPI7 cells with an epithelioid morphology and visceral endoderm-like END2 cells, both endogenously expressing functional Cx43. Cx43 protein contents were determined by Western blot analysis, whereas immunofluorescence (IF) imaging was used to assess the subcellular localization of Cx43 proteins. Dye injections were used to gain insight into the effects of propafenone on Cx43 function. RESULTS: Full-length Cx43 protein levels were dose-dependently increased after propafenone treatment and IF microscopy showed an intracellular accumulation of Cx43 protein, both on heterologously and endogenously expressed Cx43. Propafenone did not alter the Cx43 half-life, in contrast to the lysosomal inhibitor chloroquine. Finally, gap-junctional coupling was decreased by chronic propafenone treatment. CONCLUSION: We conclude that propafenone increases non-functional Cx43 protein content, resulting in its intracellular accumulation, as a side effect. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"849-861"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326637","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":"Naringenin and quercetin alter mouse rod phototransduction kinetics in a manner consistent with phosphodiesterase-6 inhibition.","authors":"Lorenzo Cangiano, Claudia Gargini, Sabrina Asteriti","doi":"10.1007/s43440-026-00835-9","DOIUrl":"10.1007/s43440-026-00835-9","url":null,"abstract":"<p><p>BACKGROUND: The flavonoids naringenin and quercetin are promising therapeutic agents for a wide variety of diseases, including inherited retinal degenerations (IRDs), thanks to their antioxidant, anti-inflammatory, and other properties. Among these are their inhibition of some phosphodiesterase (PDE) isoforms. However, it is unknown how they affect the photoreceptor-specific PDE6, which is critical for phototransduction. This interaction is key for understanding their therapeutic potential in IRDs and the risk of visual side effects more broadly. We aimed to determine if they inhibit PDE6 in living mouse retinae at pharmacologically relevant concentrations. METHODS: We used ex vivo electroretinography to record pharmacologically isolated rod a-waves from mouse retinae at 37 °C. One retina received naringenin or quercetin, while the other received the vehicle. We analysed flash response parameters: light sensitivity, time-to-peak, amplification constant (derived by fitting responses with a biophysical model), and saturating amplitude. RESULTS: Both flavonoids rapidly decreased amplification, in line with inhibition of light-activated PDE6 with a [Formula: see text] of 7.1 µM for naringenin and 15.1 µM for quercetin. Naringenin increased saturating amplitude, consistent with inhibiting dark-state PDE6. Quercetin induced a secondary slowing of phototransduction cascade termination kinetics independent of its effect on amplification, suggesting inhibition of a cascade shutdown protein. CONCLUSIONS: These findings are key to evaluating the visual safety of high-dose flavonoid therapies. They also raise the possibility that direct effects on phototransduction could play a role in their neuroprotection in IRDs. </p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"911-919"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143192","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 novel third-generation antipsychotic drug brexpiprazole affects hepatic transcription factors, serum hormone levels, and cytochrome P450 enzymes after prolonged treatment: pharmacological significance.","authors":"Przemysław J Danek, Renata Pukło, Władysława A Daniel","doi":"10.1007/s43440-026-00859-1","DOIUrl":"10.1007/s43440-026-00859-1","url":null,"abstract":"<p><strong>Background: </strong>Brexpiprazole is a third-generation antipsychotic used for the treatment of schizophrenia or as an adjunctive drug for the treatment of affective and neurological disorders. The combined treatments with brexpiprazole and other drugs that are also cytochrome P450 (CYP) substrates may lead to pharmacokinetic drug-drug interactions. Our present work aimed to investigate the effects of prolonged administration of brexpiprazole on the expression of hepatic transcription factors and CYP drug-metabolizing enzymes.</p><p><strong>Methods: </strong>Male Wistar rats received brexpiprazole (1 mg/kg ip.) for two weeks. Their livers were excised 24 h after the last dose, and the activities (HPLC), protein levels (Western blotting), and mRNAs (qRT-PCR) of CYP enzymes were measured. In parallel, the expression of hepatic transcription factors (Western blotting, qRT-PCR) and the concentration of serum hormones (ELISA) were assessed.</p><p><strong>Results: </strong>Brexpiprazole produced a broad-spectrum effect on CYP expression and activity. It enhanced the expression and activity of CYP1A, CYP2A, CYP3A1/2, and the activity of CYP2B, but decreased the expression/activity of CYP2Ds and CYP2E1. The observed changes in CYP enzymes corresponded to alterations in transcription factors: the increased expression of PXR and AhR, and decreased expression of PPARγ, LXR, and FXR. The above modifications in CYP enzymes' expression were accompanied by enhanced corticosterone and reduced T₄ serum levels.</p><p><strong>Conclusions: </strong>Brexpiprazole affects the expression of hepatic transcription factors and CYP, which may impact its own biotransformation and the metabolism of endogenous substances and concomitantly administered drugs, and lead to drug-drug interactions of pharmacological/clinical importance.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"762-774"},"PeriodicalIF":4.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841394","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}