Expert opinion on drug metabolism & toxicology最新文献_第3页

Comparison of ADMET profile between thiosemicarbazide and semicarbazide derivatives regarding anticancer properties. 硫代氨基脲与氨基脲衍生物抗癌性能的ADMET谱比较。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-17 DOI: 10.1080/17425255.2025.2520561

Łucja Justyna Walczak, Mariola Herbet

{"title":"Comparison of ADMET profile between thiosemicarbazide and semicarbazide derivatives regarding anticancer properties.","authors":"Łucja Justyna Walczak, Mariola Herbet","doi":"10.1080/17425255.2025.2520561","DOIUrl":"10.1080/17425255.2025.2520561","url":null,"abstract":"Introduction: The incidence of cancer is constantly increasing, and current cytostatics are not effective enough and cause serious side effects. Thio/semicarbazide derivatives seem to be promising candidates for anticancer drugs. This systematic review aimed to analyze comparatively the ADMET profiles of thiosemicarbazides and semicarbazides with proven antitumor activity published through August 2024.Methods: A search of PubMed, ScienceDirect and Google Scholar databases was performed. Qualified compounds were subjected to in silico analysis using ADMETlab 2.0 software. The data were statistically analyzed (Student's t-test, Mann-Whitney U test, Chi2).Results: Comparative analysis showed that semicarbazides have more favorable intestinal absorption properties and lower biological activity but have higher selectivity of action and lower risk of drug interactions. Thiosemicarbazides have a higher probability of metabolic activity with concomitant increased toxicity. These compounds show significantly higher levels of binding to plasma proteins, a lower average percentage of the unbound fraction, and a longer half-life.Conclusions: In light of anticancer therapies, thiosemicarbazides can cause increased oxidative stress and DNA damage, which is one strategy for cancer treatment. However, semicarbazides are better candidates for anticancer drug trials because of their better pharmacokinetic and pharmacodynamic profiles and lower toxicity.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287648","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}

引用次数: 0

The effect of prolonged treatment with antipsychotic drugs on cytochrome P450 - drug metabolizing enzymes. Mechanisms of action and significance for pharmacotherapy. 抗精神病药物长期治疗对细胞色素P450 -药物代谢酶的影响。作用机制及其对药物治疗的意义。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-13 DOI: 10.1080/17425255.2025.2517731

Agnieszka Basińska-Ziobroń, Przemysław Jan Danek, Władysława Anna Daniel

{"title":"The effect of prolonged treatment with antipsychotic drugs on cytochrome P450 - drug metabolizing enzymes. Mechanisms of action and significance for pharmacotherapy.","authors":"Agnieszka Basińska-Ziobroń, Przemysław Jan Danek, Władysława Anna Daniel","doi":"10.1080/17425255.2025.2517731","DOIUrl":"10.1080/17425255.2025.2517731","url":null,"abstract":"Introduction: The treatment of schizophrenia and other psychosis-related mental disorders requires long-term therapy with selected drugs possessing adequate pharmacological receptor spectra, relevant to the patient's clinical state. Antipsychotics can interact with cytochrome P450 (CYP) reciprocally affecting each other in different ways. The enzyme plays an important role in the metabolism of antipsychotics, whereas antipsychotics can affect CYP enzymes in the liver and brain.Areas covered: The effects of short and prolonged administration of antipsychotic drugs belonging to different groups (first-, second- and third-generation) on the expression and activity of CYP enzymes in the liver and brain are presented (based on PubMed 3 December 2024). Possible relations between pharmacological receptor spectra of antipsychotics and their influence on the regulation of cytochrome P450 in the liver and brain are considered. The results are discussed in the light of pharmacological and therapeutic significance.Expert opinion: During continuous treatment in vivo, the direct mechanisms (drug/metabolite binding to the CYP enzyme) overlap with the effect of antipsychotics on CYP regulation (enzyme induction or inhibition). Clinicians using the information on particular drug-CYP interaction in combination with pharmacogenetic data can make informed decisions about drug selection and dosage, ultimately advancing more effective and safer pharmacotherapy.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259681","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}

引用次数: 0

Pharmacotherapy in kidney disease: what it takes to move from general guidance to specific recommendations to stratified subgroups of patients - the tale of autosomal dominant polycystic kidney disease (ADPKD). 肾脏疾病的药物治疗：如何从一般指导转变为针对分层患者亚组的具体建议——常染色体显性多囊肾病（ADPKD）的故事

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-05-07 DOI: 10.1080/17425255.2025.2501127

Annika C Tillmann, Amin Rostami-Hodjegan, Jill Barber, Zubida M Al-Majdoub

{"title":"Pharmacotherapy in kidney disease: what it takes to move from general guidance to specific recommendations to stratified subgroups of patients - the tale of autosomal dominant polycystic kidney disease (ADPKD).","authors":"Annika C Tillmann, Amin Rostami-Hodjegan, Jill Barber, Zubida M Al-Majdoub","doi":"10.1080/17425255.2025.2501127","DOIUrl":"10.1080/17425255.2025.2501127","url":null,"abstract":"Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that leads to a range of systemic manifestations. Many of them require pharmacological interventions. Most patients receive multidrug therapy.Areas covered: The review summarizes prevalent ADPKD manifestations that might require pharmacological intervention and the most common drug therapies. It lists 2 to 3 prescribed drugs for each manifestation of ADPKD. The review identifies the drug transporters and drug-metabolizing enzymes associated with these drugs, as well as potential drug-drug interactions. To fulfill these aims, a literature search was conducted on PubMed, covering the period from 2021 to July 2024.Expert opinion: ADPKD therapy often focuses on treating a single manifestation of the disease. However, ADPKD is a complex condition that requires multidrug treatment. While doses of renally eliminated drugs are adjusted in ADPKD patients to account for renal function decline, the condition may change the expression and function of renal and hepatic drug-metabolizing enzymes and transporters, which could result in misevaluations in drug dosing in ADPKD patients and result in under- or overdosing, as well as drug-drug interactions. PBPK modeling offers a valuable tool to predict drug-drug interactions, preventing overdosing, and support precision dosing in patients with ADPKD.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"677-687"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059932","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}

引用次数: 0

DILI prediction in drug development: present and future. 药物开发中的DILI预测：现在和未来。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-04-20 DOI: 10.1080/17425255.2025.2495955

Jack Uetrecht

{"title":"DILI prediction in drug development: present and future.","authors":"Jack Uetrecht","doi":"10.1080/17425255.2025.2495955","DOIUrl":"10.1080/17425255.2025.2495955","url":null,"abstract":"Introduction: Idiosyncratic drug-induced liver injury (iDILI) results in significant patient morbidity and significantly increases the risk of drug development. The current methods to screen for iDILI risk are inadequate.Areas covered: The general mechanism of iDILI and the current methods to screen for iDILI are reviewed. Then the potential for new biomarkers is explored.Expert opinion: Better biomarkers of iDILI risk should be based on the mechanism of iDILI. In general, it is an adaptive immune response, specifically CD8+ cytotoxic T cells, that is responsible for hepatocyte cell death, not direct toxicity of the drug. Therefore, in vitro cytotoxicity assays represent an artifact not the mechanism of iDILI. Activation of the adaptive immune response leading to iDILI requires an innate immune response, in particular activation of antigen presenting cells. The innate immune response is immediate and unlikely to be idiosyncratic. For example, studies have found that incubation of hepatocytes with drugs causes the release of molecules that activate THP-1-derived macrophages. The response of hepatocytes, the release of damage-associated molecular pattern molecules (DAMPs), especially in extracellular vesicles, and the response of antigen presenting cells (APCs) are likely to provide better biomarkers of iDILI risk.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"665-676"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035828","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}

引用次数: 0

The influence of female sex and estrogens on drug pharmacokinetics: what is the evidence? 女性和雌激素对药物药代动力学的影响：证据是什么？

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-03-20 DOI: 10.1080/17425255.2025.2481891

E L Bosch, I E C Sommer, D J Touw

{"title":"The influence of female sex and estrogens on drug pharmacokinetics: what is the evidence?","authors":"E L Bosch, I E C Sommer, D J Touw","doi":"10.1080/17425255.2025.2481891","DOIUrl":"10.1080/17425255.2025.2481891","url":null,"abstract":"Introduction: Pharmacological research has traditionally been skewed toward male subjects, leading to uniform treatment guidelines for both men and women that assume similar drug pharmacokinetics across sexes. This oversight contributes to women experiencing adverse drug reactions on average twice as often as men. More recent studies have revealed significant pharmacokinetic differences between the sexes, partly due to different sex hormone levels. Additionally, intraindividual differences in women have been observed due to fluctuating estrogen levels, impacting important aspects of drug pharmacokinetics.Areas covered: This review highlights key sex differences in drug pharmacokinetics, focusing on absorption, distribution, metabolism, and excretion. A particular emphasis is placed on the role of cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes in drug metabolism, and on the role of P-glycoprotein (P-gp). The impact of estrogens is reviewed by exploring how drug pharmacokinetics change over the menstrual cycle, before and after menopause, and with estrogen-containing medications.Expert opinion: Personalized dosing based on sex and estrogen levels is important for improving treatment outcomes in female drug users. Clinical trials of drugs likely affected by these factors should incorporate pharmacokinetic studies that distinguish between sexes and evaluate the impact of estrogens, aiming to develop optimized dosing regimens.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"637-647"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665633","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}

引用次数: 0

Pharmacokinetic considerations for gonadotropin-releasing hormone agonists and antagonists to treat endometriosis. 促性腺激素释放激素激动剂和拮抗剂治疗子宫内膜异位症的药代动力学考虑。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-05-06 DOI: 10.1080/17425255.2025.2499550

Anna Maria Paoletti, Manuela Neri, Monica Pilloni, Maria Francesca Marotto, Elena Giancane, Valerio Vallerino, Bruno Piras, Giulia Melis, Virginia Melis, Michele Danilo Maria Masciale, Enrica Murgia, Gian Benedetto Melis

{"title":"Pharmacokinetic considerations for gonadotropin-releasing hormone agonists and antagonists to treat endometriosis.","authors":"Anna Maria Paoletti, Manuela Neri, Monica Pilloni, Maria Francesca Marotto, Elena Giancane, Valerio Vallerino, Bruno Piras, Giulia Melis, Virginia Melis, Michele Danilo Maria Masciale, Enrica Murgia, Gian Benedetto Melis","doi":"10.1080/17425255.2025.2499550","DOIUrl":"10.1080/17425255.2025.2499550","url":null,"abstract":"Introduction: Endometriosis is a chronic disease characterized by endometriotic cells implanted outside the uterus triggering a chronic inflammatory state. Estradiol stimulates the endometriotic implants, which overexpress estrogen receptor β. Lowering estradiol levels to a range within 40-50 pg/ml allows antagonizing the growth of endometriotic implants and counteracting its-related disabling symptoms.Areas covered: By blocking the Gonadotropin-Releasing-Hormone (GnRH) receptors, GnRHagonists, peptide GnRHantagonists, non-peptide GnRHantagonists induce hypoestrogenism, due to the suppression of pituitary gonadotropins. This manuscript provides the results of an electronic literature search on pharmacological features of GnRHagonists and GnRHantagonists to treat endometriosis. Hypoestrogenism-dependent side effects can be counteracted by concomitant estrogen and progestin compounds (add-back therapy). GnRHagonists chronic administration induces hypoestrogenism after 10-12 days, since initial administrations stimulate gonadotropin rise (flare-up effect). Peptide GnRHantagonists quickly block GnRH-receptors inducing an immediate hypoestrogenism. Similarly to GnRHagonists, their peptide structure impedes the oral administration. The non-peptide GnRHantagonists have the advantage both of being taken orally and inducing a rapid dose-dependent hypoestrogenism.Expert opinion: GnRHagonists and peptide GnRHantagonists are effective to treat endometriosis, but require complex ways of administration. Non-peptide GnRHantagonists offer more important prospects in the tailored medical treatment of endometriosis, given their rapid onset of action and their oral way of administration.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"649-663"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003924","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}

引用次数: 0

The impact of CBR3 (rs1056892) and ABCC1 (rs45511401) genetic polymorphisms on doxorubicin-induced cardiotoxicity and the potential role of brain natriuretic peptide as an early cardiac biomarker in breast cancer patients. CBR3 （rs1056892）和ABCC1 （rs45511401）遗传多态性对阿霉素诱导的心脏毒性的影响，以及脑利钠肽作为乳腺癌患者早期心脏生物标志物的潜在作用。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-04-11 DOI: 10.1080/17425255.2025.2490736

Enas A El-Shorbagy, Noha A El-Bassiouny, Amira B Kassem, Ahmad Salahuddin, Mahmoud Mohamed Kamel, Ahmed El Bastawisy, Nermeen Nabeel Abuelsoud

{"title":"The impact of CBR3 (rs1056892) and ABCC1 (rs45511401) genetic polymorphisms on doxorubicin-induced cardiotoxicity and the potential role of brain natriuretic peptide as an early cardiac biomarker in breast cancer patients.","authors":"Enas A El-Shorbagy, Noha A El-Bassiouny, Amira B Kassem, Ahmad Salahuddin, Mahmoud Mohamed Kamel, Ahmed El Bastawisy, Nermeen Nabeel Abuelsoud","doi":"10.1080/17425255.2025.2490736","DOIUrl":"10.1080/17425255.2025.2490736","url":null,"abstract":"Background: Doxorubicin (DOX), a potent antineoplastic drug, can induce cardiotoxicity through its cardiotoxic metabolites catalyzed by CBR 3 and its accumulation in cardiac tissue via the ABCC1 transporter. Here, we investigated CBR3 and ABCC1 genetic polymorphisms affecting doxorubicin cardiotoxicity in breast cancer patients and explored the potential role of brain natriuretic peptide (BNP) as an early cardiac biomarker.Methods: One hundred Breast cancer patients are receiving DOX treatment. Blood samples were analyzed for CBR3 and ABCC1 gene polymorphisms and echocardiography and BNP biomarkers were used to assess cardiotoxicity at baseline and three months post-DOX treatment.Results: Following the DOX treatment, CBR3 genotypes showed significant differences in BNP levels and delta BNP (p = 0.001 and 0.014, respectively). There was a significant association between different CBR3 genotypes and BNP levels after DOX (p = 0.001) and delta BNP (p = 0.01), with AA genotypes associated with cardiotoxicity. ABCC1 was not associated significantly with cardiotoxicity (p = 0.67). There was a statistically significant difference between CBR3 genotypes and the occurrence of anemia (p = 0.023).Conclusion: Detecting CBR3 genetic polymorphisms is crucial for assessing cardiotoxicity before administering DOX, and monitoring BNP levels helps early detection. CBR3 is also associated with DOX anemia.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"737-749"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001950","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}

引用次数: 0

Management of polypharmacy and potential drug-drug interactions in people with HIV and cancer: insights from a 4-year multidisciplinary clinic experience. 艾滋病病毒感染者和癌症患者的多药治疗和潜在药物相互作用管理：4 年多学科门诊经验的启示。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-04-07 DOI: 10.1080/17425255.2025.2489393

Dario Cattaneo, Anna Lisa Ridolfo, Davide Dalu, Chiara Pruneri, Andrea Giacomelli, Maria Vittoria Cossu, Lorenzo Ruggieri, Cinzia Fasola, Aurora Civati, Alberto Dolci, Nicla La Verde, Spinello Antinori, Andrea Gori, Cristina Gervasoni

{"title":"Management of polypharmacy and potential drug-drug interactions in people with HIV and cancer: insights from a 4-year multidisciplinary clinic experience.","authors":"Dario Cattaneo, Anna Lisa Ridolfo, Davide Dalu, Chiara Pruneri, Andrea Giacomelli, Maria Vittoria Cossu, Lorenzo Ruggieri, Cinzia Fasola, Aurora Civati, Alberto Dolci, Nicla La Verde, Spinello Antinori, Andrea Gori, Cristina Gervasoni","doi":"10.1080/17425255.2025.2489393","DOIUrl":"10.1080/17425255.2025.2489393","url":null,"abstract":"Background: People with HIV and cancer (PWHC) are often treated with different combinations of antiretroviral and oncology drugs, frequently associated with other co-medications; this significantly increases the risk of potential drug-drug interactions (DDIs).Research design and methods: A prospective observational study has been carried out from May 2020 to May 2024 to describe the management of therapies in PWHC in an outpatient clinic.Results: 140 PWHC treated with 42 different antiretroviral and 59 oncology regimens were enrolled, resulting in the identification of 410 DDIs. Of these, 8% were scored as red-flag DDIs). Among antiretroviral medications, 77% of red-flag DDIs involved ritonavir or cobicistat. Paclitaxel was the oncology drug most frequently associated with red-flag-DDIs (77%). Proton pump inhibitors (PPIs) were involved in 19% of red-flag and 32 of orange-flag DDIs. The most frequent recommendations included performing an electrocardiogram (38%), conducting therapeutic drug monitoring (31%), discontinuing PPIs (29%) and/or adjusting the timing of drug intake (28%).Conclusions: A high prevalence of polypharmacy and clinically relevant DDIs was observed in our cohort of PWHC. A multidisciplinary team could play a pivotal role in optimizing pharmacological therapies in this clinical setting, for example, by reducing the use of PPIs and booster-based antiretroviral regimens.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"729-736"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789456","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}

引用次数: 0

Epigenetics is involved in the pleiotropic effects of statins. 他汀类药物的多效性与表观遗传学有关。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-04-17 DOI: 10.1080/17425255.2025.2491732

Cezar Kayzuka, Vitória Carolina Rondon-Pereira, Cecilia Nogueira Tavares, Mayra Pacheco Pachado, Fabiola Zakia Monica, Jose Eduardo Tanus-Santos, Riccardo Lacchini

{"title":"Epigenetics is involved in the pleiotropic effects of statins.","authors":"Cezar Kayzuka, Vitória Carolina Rondon-Pereira, Cecilia Nogueira Tavares, Mayra Pacheco Pachado, Fabiola Zakia Monica, Jose Eduardo Tanus-Santos, Riccardo Lacchini","doi":"10.1080/17425255.2025.2491732","DOIUrl":"10.1080/17425255.2025.2491732","url":null,"abstract":"Introduction: Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear.Area covered: This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024.Expert opinion: The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"689-701"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061222","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}

引用次数: 0

A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury: current capabilities and challenges for future predictivity. 探索已知或假设的T细胞介导的药物引起的肝损伤的机制模型：目前的能力和未来预测的挑战。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-06-01 Epub Date: 2025-05-06 DOI: 10.1080/17425255.2025.2499551

Lara Clemens, Christina Battista, Zackary R Kenz, Lisl K M Shoda

{"title":"A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury: current capabilities and challenges for future predictivity.","authors":"Lara Clemens, Christina Battista, Zackary R Kenz, Lisl K M Shoda","doi":"10.1080/17425255.2025.2499551","DOIUrl":"10.1080/17425255.2025.2499551","url":null,"abstract":"Background: Drug-induced liver injury (DILI) is an adverse event whose emergence can slow or halt drug development programs. Adaptive immune responses have been implicated for several DILI compounds, and drug-specific T cell responses have been characterized, but there are still many unknowns. We describe the extension of a quantitative systems toxicology (QST) model of DILI to include CD8+ T cell-mediated DILI.Research design and methods: To overcome deficits in quantitative data characterizing CD8+ T cell-mediated DILI, a translational strategy leveraged a well-defined mouse ovalbumin (OVA) antigen model and adapted it to represent mouse amodiaquine (AQ)-specific CD8+ T cell-mediated DILI, with further adaptations to represent human AQ-specific CD8+ T cell-mediated DILI.Results: DILIsym reproduced published data characterizing mouse OVA-specific CD8+ T cell-mediated hepatotoxicity, mouse AQ-specific CD8+ T cell-mediated DILI, and human AQ-specific CD8+ T cell-mediated DILI. Development identified main drivers of the CD8+ T cell response, as well as areas where in vitro assay data could inform the simulation of additional compounds.Conclusions: The DILIsym CD8+ T cell sub-model is well-positioned for systematic testing to improve our understanding of CD8+ T cell-mediated DILI. It is not yet predictive but indicates a promising direction to reduce DILI events in drug development.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"717-727"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060488","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}

引用次数: 0