Pharmacological Reports最新文献

{"title":"The effect of phencyclidine-mediated blockade of NMDA receptors in the early postnatal period on glutathione and sulfur amino acid levels in the rat brain as a potential causative factor of schizophrenia-like behavior in adulthood.","authors":"Elżbieta Lorenc-Koci, Magdalena Górny, Grażyna Chwatko, Kinga Kamińska, Małgorzata Iciek, Zofia Rogóż","doi":"10.1007/s43440-024-00607-3","DOIUrl":"10.1007/s43440-024-00607-3","url":null,"abstract":"<p><strong>Background: </strong>Phencyclidine, an NMDA receptor antagonist, is frequently used to model behavioral and neurochemical changes correlated with schizophrenia in laboratory animals. The present study aimed to examine the effects of repeated administration of phencyclidine during early postnatal development on the contents of glutathione and sulfur-containing amino acids, as well as the activity of antioxidant enzymes in the brain of 12-day-old rats, and schizophrenia-like symptoms in adulthood.</p><p><strong>Methods: </strong>Male Sprague-Dawley pups were administered phencyclidine (10 mg/kg) or saline subcutaneously on the postnatal days p2, p6, p9 and p12. In 12-day-old pups, 4 h after the last dose of phencyclidine, the levels of glutathione, cysteine, methionine, and homocysteine, and the enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were measured in the frontal cortex, hippocampus, and striatum. In 70-72-day-old rats, schizophrenia-like symptoms were assessed using behavioral tests.</p><p><strong>Results: </strong>Biochemical data showed that perinatal phencyclidine treatment significantly reduced glutathione and cysteine levels in all brain structures studied, methionine was diminished in the striatum, and homocysteine in both the frontal cortex and striatum. GR activity was increased in the frontal cortex while SODactivity was decreased in the hippocampus. Behaviorally, perinatal phencyclidine induced long-term deficits in social and cognitive function and a decrease in locomotor activity assessed as the time of walking. Finally, perinatal treatment with phencyclidine resulted in a significant reduction in body weight gain over time.</p><p><strong>Conclusion: </strong>Our research provides further evidence for the usefulness of the phencyclidine-induced neurodevelopmental model of schizophrenia for studying the pathogenesis of schizophrenia.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"863-877"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432479","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":"Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases.","authors":"Veerta Sharma, Prateek Sharma, Thakur Gurjeet Singh","doi":"10.1007/s43440-024-00613-5","DOIUrl":"10.1007/s43440-024-00613-5","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) pose a significant issue in healthcare, needing a thorough knowledge of their complex molecular mechanisms. A diverse set of cell signaling mediators and their interactions play critical roles in neuroinflammation. The release of pro-inflammatory mediators in response to neural dysfunction is detrimental to normal cell survival. Moreover, the important role of nuclear factor-κB (NF-κB) in the central nervous system through Toll-like receptor (TLR) activation has been well established. Therefore, through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (TLR-4/NF-κB inhibitors) and neurodegeneration encompassing Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and stroke. Insights garnered from this exploration underscore the potential of TLR-4 as a therapeutic target. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. This review thus serves as a roadmap, guiding future research endeavors toward innovative strategies for combatting the complex interplay between TLR-4 signaling and NDDs.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"679-692"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141451140","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":"Presynaptic antiseizure medications - basic mechanisms and clues for their rational combinations.","authors":"Ewa K Czapińska-Ciepiela, Jarogniew Łuszczki, Piotr Czapiński, Stanisław J Czuczwar, Władysław Lasoń","doi":"10.1007/s43440-024-00603-7","DOIUrl":"10.1007/s43440-024-00603-7","url":null,"abstract":"<p><p>Among clinically highly efficient antiseizure medications (ASMs) there are modifiers of the presynaptic release machinery. Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels. In this paper, we present recent progress in understanding the significance of presynaptic release machinery in the neurochemical mechanisms of epilepsy and ASMs. Furthermore, we discuss whether the knowledge of the basic mechanisms of the presynaptically acting ASMs might help establish a rational polytherapy for drug-resistant epilepsy.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"623-643"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074668","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":"A derivative of 3-(1,3-diarylallylidene)oxindoles inhibits dextran sulfate sodium-induced colitis in mice.","authors":"Young-Jin Jeong, Hae-Ri Lee, Sun-Ae Park, Joong-Woon Lee, Lee Kyung Kim, Hee Jung Kim, Jae Hong Seo, Tae-Hwe Heo","doi":"10.1007/s43440-024-00616-2","DOIUrl":"10.1007/s43440-024-00616-2","url":null,"abstract":"<p><strong>Background: </strong>IA-0130 is a derivative of 3-(1,3-diarylallylidene)oxindoles, which is a selective estrogen receptor modulator (SERM). A previous study demonstrated that SERM exhibits anti-inflammatory effects on colitis by promoting the anti-inflammatory phenotype of monocytes in murine colitis. However, the therapeutic effects of oxindole on colitis remain unknown. Therefore, we evaluated the efficacy of IA-0130 on dextran sulfate sodium (DSS)-induced mouse colitis.</p><p><strong>Methods: </strong>The DSS-induced colitis mouse model was established by administration of 2.5% DSS for 5 days. Mice were orally administered with IA-0130 (0.01 mg/kg or 0.1 mg/kg) or cyclosporin A (CsA; 30 mg/kg). Body weight, disease activity index score and colon length of mice were calculated and histological features of mouse colonic tissues were analyzed using hematoxylin and eosin staining. The expression of inflammatory cytokines and tight junction (TJ) proteins were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay. The expression of interleukin-6 (IL-6) signaling molecules in colonic tissues were investigated using Western blotting and immunohistochemistry (IHC).</p><p><strong>Results: </strong>IA-0130 (0.1 mg/kg) and CsA (30 mg/kg) prevented colitis symptom, including weight loss, bleeding, colon shortening, and expression of pro-inflammatory cytokines in colon tissues. IA-0130 treatment regulated the mouse intestinal barrier permeability and inhibited abnormal TJ protein expression. IA-0130 down-regulated IL-6 expression and prevented the phosphorylation of signaling molecules in colonic tissues.</p><p><strong>Conclusions: </strong>This study demonstrated that IA-0130 suppressed colitis progression by inhibiting the gp130 signaling pathway and expression of pro-inflammatory cytokines, and maintaining TJ integrity.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"851-862"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446761","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":"Mitochondrial targeted antioxidants as potential therapy for huntington's disease.","authors":"Shubham Upadhayay, Puneet Kumar","doi":"10.1007/s43440-024-00619-z","DOIUrl":"10.1007/s43440-024-00619-z","url":null,"abstract":"<p><p>Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"693-713"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563974","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":"MDPV (3,4-methylenedioxypyrovalerone) administered to mice during development of the central nervous system produces persistent learning and memory impairments.","authors":"Katarzyna Kuczyńska, Katarzyna Bartkowska, Ruzanna Djavadian, Ewa Zwierzyńska, Jakub Wojcieszak","doi":"10.1007/s43440-024-00599-0","DOIUrl":"10.1007/s43440-024-00599-0","url":null,"abstract":"<p><strong>Background: </strong>Synthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice.</p><p><strong>Methods: </strong>All experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11-20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot.</p><p><strong>Results: </strong>Exposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent.</p><p><strong>Conclusions: </strong>MDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"519-534"},"PeriodicalIF":3.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11126454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899008","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":"Liquid chromatography-tandem mass spectrometry method for mycophenolic acid and its glucuronide determination in saliva samples from children with nephrotic syndrome.","authors":"Joanna Sobiak, Matylda Resztak, Weronika Sikora, Jacek Zachwieja, Danuta Ostalska-Nowicka","doi":"10.1007/s43440-024-00574-9","DOIUrl":"10.1007/s43440-024-00574-9","url":null,"abstract":"<p><strong>Background: </strong>Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study describes the liquid chromatography tandem mass spectrometry (LC-MS/MS) method developed for saliva MPA and MPAG determination in children with nephrotic syndrome.</p><p><strong>Methods: </strong>The mobile phase consisted of methanol and water at gradient flow, both with 0.1% formic acid. Firstly, 100 µL of saliva was evaporated at 45 °C for 2 h to dryness, secondly, it was reconstituted in the mobile phase, and finally 10 µL was injected into the LC-MS/MS system. Saliva from ten children with nephrotic syndrome treated with mycophenolate mofetil was collected with Salivette^®.</p><p><strong>Results: </strong>For MPA and MPAG, within the 2-500 ng/mL range, the method was selective, specific, accurate and precise within-run and between-run. No carry-over and matrix effects were observed. Stability tests showed that MPA and MPAG were stable in saliva samples if stored for 2 h at room temperature, 18 h at 4 °C, and at least 5 months at - 80 °C as well as after three freeze-thaw cycles, in a dry extract for 16 h at 4 °C, and for 8 h at 15 °C in the autosampler. The analytes were not adsorbed onto Salivette^® cotton swabs. For concentrations above 500 ng/mL, the samples may be diluted twofold. In children, saliva MPA and MPAG were within the ranges of 4.6-531.8 ng/mL and 10.7-183.7 ng/mL, respectively.</p><p><strong>Conclusions: </strong>The evaluated LC-MS/MS method has met the validation requirements for saliva MPA and MPAG determination in children with nephrotic syndrome. Further studies are needed to explore plasma-saliva correlations and assess their potential contribution to MPA monitoring.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"600-611"},"PeriodicalIF":3.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11126467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140132182","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":"Mechanistic correlation of molecular pathways in obesity-mediated stroke pathogenesis","authors":"Heena Khan, Chanchal Tiwari, Palak Kalra, Daksha Vyas, Amarjot Kaur Grewal, Thakur Gurjeet Singh","doi":"10.1007/s43440-024-00590-9","DOIUrl":"https://doi.org/10.1007/s43440-024-00590-9","url":null,"abstract":"<p>Obesity, a prominent risk factor for the development of heart attacks and several cardiovascular ailments. Obesity ranks as the second most significant avoidable contributor to mortality, whereas stroke stands as the second leading cause of death on a global scale. While changes in lifestyle have been demonstrated to have significant impacts on weight management, the long-term weight loss remains challenging, and the global prevalence of obesity continues to rise. The pathophysiology of obesity has been extensively studied during the last few decades, and an increasing number of signal transduction pathways have been linked to obesity preclinically. This review is focused on signaling pathways, and their respective functions in regulating the consumption of fatty food as well as accumulation of adipose tissue, and the resulting morphological and cognitive changes in the brain of individuals with obesity. We have also emphasized the recent progress in the mechanisms behind the emergence of obesity, as elucidated by both experimental and clinical investigations. The mounting understanding of signaling transduction may shed light on the future course of obesity research as we move into a new era of precision medicine.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"31 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624412","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":"Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice","authors":"Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Michal Santocki, Yana Babii, Katarzyna Kaczorowska","doi":"10.1007/s43440-024-00588-3","DOIUrl":"https://doi.org/10.1007/s43440-024-00588-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu₅) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu₅ NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (<i>ip</i>) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (<i>ip</i>) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Partial mGlu₅ receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced <i>(R)</i>-ketamine action in mice, indicating both substances’ convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"7 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624648","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":"Pharmacokinetic interaction between regorafenib and atorvastatin in rats","authors":"Danuta Szkutnik-Fiedler, Edyta Szałek, Filip Otto, Andrzej Czyrski, Marta Karaźniewicz-Łada, Anna Wolc, Edmund Grześkowiak, Konrad Lewandowski, Agnieszka Karbownik","doi":"10.1007/s43440-024-00570-z","DOIUrl":"https://doi.org/10.1007/s43440-024-00570-z","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug–drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (I_REG+ATO), a carrier with regorafenib (II_REG), and atorvastatin with a carrier (III_ATO). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the I_REG+ATO group, the <i>C</i>_max, AUC_0–<i>t</i>, and AUC_0–∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the <i>C</i>_max, AUC_0–<i>t</i>, and AUC_0–∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC_0–<i>t</i> and AUC_0–∞ of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.</p><h3 data-test=\"abstract-sub-heading\">Graphical abstract</h3>\u0000","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":"22 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624408","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}