Current drug metabolism最新文献

{"title":"Pharmacokinetic Interactions of Paxlovid Involving CYP3A Enzymes and P-gp Transporter: An Overview of Clinical Data.","authors":"Naina Mohamed Pakkir Maideen, Krishnaveni Kandasamy, Rajkapoor Balasubramanian","doi":"10.2174/0113892002320326250123082112","DOIUrl":"https://doi.org/10.2174/0113892002320326250123082112","url":null,"abstract":"<p><strong>Background: </strong>The US FDA has approved paxlovid, a combination of nirmatrelvir and ritonavir, as the first oral treatment for the management of mild-to-moderate COVID-19 patients.</p><p><strong>Objective: </strong>The purpose of this review article is to explore the clinical data that is currently available regarding the drug-drug interactions (DDIs) of paxlovid with various medications.</p><p><strong>Methods: </strong>Keywords, such as drug interactions, paxlovid, ritonavir, nirmatrelvir, pharmacokinetic interactions, CYP3A, and P-glycoprotein, were used to search online databases, including LitCOVID, Scopus, Embase, EBSCO host, Google Scholar, ScienceDirect, Cochrane Library, and reference lists.</p><p><strong>Results: </strong>Paxlovid interacted with a variety of medications due to strong inhibition of CYP3A4 and P-gp transporter protein by ritonavir and the dual function of nirmatrelvir as a substrate and inhibitor of CYP3A enzymes and P-gp transporter protein. Numerous case reports and other studies determined that the risk of toxicities of several drugs, including anticoagulants (warfarin, rivaroxaban), calcium channel blockers (nifedipine, manidipine, verapamil), statins (atorvastatin), immunosuppressants (tacrolimus), antiarrhythmics (amiodarone), antipsychotics (clozapine, quetiapine), and ranolazine have been enhanced by the concomitant administration of paxlovid.</p><p><strong>Conclusion: </strong>Adverse effects of paxlovid from DDIs can range from less-than-ideal therapeutic responses to potentially fatal toxicities. Effective management requires close observation, adjustments to dosage, and assessment of substitute treatments. Collaboration between pharmacists and other medical professionals is necessary to guarantee effective and safe treatment outcomes of paxlovid therapy.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Shenmai Injection on the Pharmacokinetics of Dasatinib: An In-Depth In vivo Analysis Utilizing UPLC-MS/MS Technique.","authors":"Weina Ma, Ling Li, Zhihui Li, Jungang Guo, Yifei Zhu, Liye Ge, Rong Wang, Lei Lv","doi":"10.2174/0113892002336775250108112738","DOIUrl":"https://doi.org/10.2174/0113892002336775250108112738","url":null,"abstract":"<p><strong>Background: </strong>Dasatinib has been widely used in the treatment of a variety of cancers, such as lung cancer and acute myeloid leukemia. Shenmai injection is a traditional Chinese medicine injection that is often used in antitumor adjuvant therapy. In recent years, dasatinib combined with Shenmai injection has been increasingly used to treat tumors clinically. However, the potential risks and benefits of co-administering Shenmai injection and dasatinib are unclear.</p><p><strong>Objective: </strong>The study aimed to investigate the potential influence of Shenmai injection on dasatinib pharmacokinetics.</p><p><strong>Methods: </strong>Twelve rats were selected and randomly divided into two groups: dasatinib alone and a combination of dasatinib and Shenmai injection. To measure the concentration of dasatinib in rat plasma, blood samples were obtained from the orbital vein. Using ultra-performance liquid chromatography-tandem mass spectrometry, the concentration of dasatinib was determined to obtain pharmacokinetic parameters.</p><p><strong>Results: </strong>Compared to the dasatinib alone administration, the maximum concentration of the dasatinib plus Shenmai injection administration was decreased (355.9 ± 194.9 vs. 199.2 ± 73.8 ng·mL-1) (P < 0.05). Moreover, the area under the moment curve (3867.0 ± 2141.9 vs. 6355.3 ± 3311.6 ng·mL-1·h2) and mean residence time (3.7 ± 1.2 vs. 6.5 ± 3.1 h) showed a statistically significant increase (P < 0.05).</p><p><strong>Conclusion: </strong>The study revealed that Shenmai injection might have the capacity to slow down the absorption rate of dasatinib and could extend the retention period of dasatinib in the body, resulting in stabilized blood drug concentrations and a reduction in adverse drug reactions.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hallmarks of Quercetin Benefits as a Functional Supplementary in the Management of Diabetes Mellitus-Related Maladies: From Basic to Clinical Applications.","authors":"Faegheh Farhadi, Fariba Sharififar, Mandana Jafari, Vafa Baradaran Rahimi, Nafiseh Askari, Vahid Reza Askari","doi":"10.2174/0113892002339410250108031621","DOIUrl":"https://doi.org/10.2174/0113892002339410250108031621","url":null,"abstract":"<p><p>Quercetin (QE), a particular flavonoid, is well known for its medicinal effects, including anti-oxidant, hypoglycemic, and anti-inflammatory effects. In this review, the findings of QE effects on diabetes STZinduced, alloxan-induced, and its complications have been summarized with a particular focus on in vitro, in vivo, and clinical trials. Consequently, QE mediates several mechanisms, including ameliorating tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β, IL-8, and IL-10 expression, increasing insulin glucose uptake to inhibit insulin resistance. Moreover, QE stimulates insulin secretion and attenuates insulin resistance through various pathways, namely transient KATP channel, motivating peroxisome proliferator-activated receptor expression, increasing glucose transporter-4, and decreasing inducible nitric oxide synthase in skeletal muscle. QE has protective effects on the complications caused by diabetes, such as polycystic ovary syndrome, high-fat diet-induced obesity, diabetic-induced hepatic damage, vascular inflammation, nephropathy, and neuropathy.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Drug-Drug Interactions between Losartan and Carbamazepine: A Pharmacokinetic and Pharmacodynamic Study.","authors":"Shruthi A Sundargowda, Sunil Kumar Kadiri","doi":"10.2174/0113892002358068250119052940","DOIUrl":"https://doi.org/10.2174/0113892002358068250119052940","url":null,"abstract":"<p><strong>Background: </strong>Hypertension, which affects 1.28 billion people globally aged 30 to 79, is characterized by continuously high blood pressure (140/90 or more) and raises the risk of premature death. Losartan, an angiotensin receptor blocker (ARB), is suggested for patients under the age of 55 who cannot take ACE inhibitors as a first treatment option. Epilepsy, a chronic neurological illness marked by repeated seizures, affects more than 50 million individuals worldwide and is the third most common chronic brain disorder. Both hypertension and epilepsy are frequent chronic illnesses, with increased blood pressure greatly raising the risk of epilepsy due to its relationship with cerebrovascular disease, doubling the risk when compared to people with normal blood pressure.</p><p><strong>Objective: </strong>The effect on pharmacokinetic and pharmacodynamics of losartan on concomitant administration with carbamazepine was investigated.</p><p><strong>Materials and methods: </strong>Wistar rats of either sex, with a minimum of six animals per group, were used in the investigation. The rats were treated with Losartan and Losartan-Carbamazepine for 30 days. Blood samples were taken via retro-orbital plexus at 0, 1, 2, 4, 6, and 12 hours after treatment concluded, and they were subjected to high-performance liquid chromatography for plasma analysis to calculate AUC, t1/2, and Clearance. A pharmacodynamic evaluation was done by inducing hypertension in rats using a 10% fructose solution and the effect of pretreated Losartan and Losartan-Carbamazepine on blood pressure was determined.</p><p><strong>Results: </strong>In the Losartan and Carbamazepine treated group, there was a reduction in the AUC and t1/2 and a reported increase in the clearance value compared to Losartan alone treated rats. In fructose-induced hypertension model to evaluate the effect of losartan and carbamazepine on BP showed an increase in mean arterial pressure, plasma glucose, and a reduction in triglycerides level was noted in comparison to Losartan alone treated rats indicating therapeutic failure of Losartan.</p><p><strong>Conclusion: </strong>Based on these studies, it is concluded that CBZ has reduced the effectiveness of losartan and therefore, co-administration of these drugs should be avoided.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Five Natural Anthraquinone Compounds as Potent Inhibitors against CYP1B1: Implications for Cancer Treatment.","authors":"Zujia Chen, Zhixiang Xu, Xiaodong Chen, Xintong Guan, Jie Du, Jia Hui Zhang, Chang Yuan Wang, Jingjing Wu","doi":"10.2174/0113892002329282250108163208","DOIUrl":"https://doi.org/10.2174/0113892002329282250108163208","url":null,"abstract":"<p><strong>Background: </strong>Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme that is overexpressed in many tumors and is associated with tumor development and acquired resistance. Few studies have reported that anthraquinone compounds have inhibitory activity against the CYP1B1 enzyme. Cassiae semen (Leguminosae) is a well-known traditional Chinese medicine containing more than 70 compounds. The crude extracts and pure compounds of Cassiae semen have been widely used in preclinical and clinical practice for their beneficial effects, such as neuroprotective, hepatoprotective, antimicrobial, antioxidant, and hypotensive effects. Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein are important active natural anthraquinones in Cassiae semen.</p><p><strong>Objective: </strong>Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein have a wide range of pharmacological activities and have been found to have good anti-tumor and antioxidant effects. However, the underlying mechanisms of these pharmacological activities remain poorly understood. This study aimed to investigate the inhibitory effects of five natural anthraquinones on the activity of CYP1B1 and to analyze the structure- activity relationship of these compounds.</p><p><strong>Materials and methods: </strong>In this study, 7-ethoxyresorufin O-deethylation (EROD) was used as the fluorescent substrate of CYP1B1 to investigate the inhibition effect, and molecular docking was performed to further determine the structural-activity relationship of the compound molecules.</p><p><strong>Results: </strong>We found that aloe-emodin and chrysophanol had strong inhibitory effects on CYP1B1 with IC50 values of 0.28 and 0.34μM, respectively, while obtusifolin and aurantio-obtusin had IC50 values of 0.77μM and 9.11μM, respectively. The structural activity analysis showed that the inhibition strength was related to the position of the hydroxyl group substitution and the number of methoxy group substitutions. Rhein containing one carboxyl group showed the weakest inhibition of 23.72μM. The inhibition kinetics showed that all five compounds belonged to the non-competitive inhibition model. The inhibition kinetics revealed that all five compounds exhibited the non-competitive inhibition model.</p><p><strong>Conclusion: </strong>The present study provided a comprehensive analysis of the inhibitory effects of five natural anthraquinones, namely aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin and rhein, on CYP1B1 activity, and elucidated the structure-activity relationship. Molecular docking simulations further revealed the specific amino acid residues within the active site of CYP1B1, where these compounds exerted their actions. These findings offer novel insights into investigating the potential antitumor properties of natural anthraquinones.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tacrolimus, Cytochrome P450, Interactions with Food Variables in Organ Transplant Recipients; A Current and Comprehensive Review.","authors":"Zahra Tolou-Ghamari","doi":"10.2174/0113892002328742241210102522","DOIUrl":"https://doi.org/10.2174/0113892002328742241210102522","url":null,"abstract":"<p><p>The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many features associated with food parameters like phytochemicals, juices, and fruits. This review article summarizes the findings of previous studies to help predict the efficacy or side effects of tacrolimus in the presence of food variables. From the commencement of databases associated with the topic of interest to 26 October 2024, all relevant articles were searched through PubMed, Scopus, and Web of Science. The suggested therapeutic range for tacrolimus trough concentration (C) was reported as 5-15 ng/ml blood. Tacrolimus interaction with food variables could significantly change C after organ transplantation. For example, grapefruit juice could increase tacrolimus C due to CYP enzyme inhibition. Toxicity such as nephrotoxicity could result from turmeric and other herbal or food products. By inhibiting tacrolimus-metabolizing enzymes and transporters, a high intake of vegetables could increase the risk of adverse effects. Secondary metabolites of vegetables could lead to toxicity in patients with tacrolimus. Furthermore, grapefruit juice, citrus fruits, turmeric, and pomegranate juice could change clinical pharmacokinetics parameters such as Tmax, Cmax, AUC, and C of tacrolimus after organ transplantation. Bioavailability of tacrolimus might be decreased by induction of the CYP450 system and P-gp efflux pump due to cranberry, rooibos tea, and boldo. Increased inhibitory effect on CYP450 system and/or P-gp efflux pump by grapefruit juice, schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger could increase bioavailability of tacrolimus. A vigilant immunosuppressive strategy accompanied by scheduled therapeutic drug monitoring is recommended before and after transplant surgery.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Insights into Nano-mediated siRNA Drug Delivery.","authors":"Venkateshwaran Krishnaswami, Kumar Janakiraman, Vaidevi Sethuraman, Jacob Raja, Selvakumar Muruganantham, Senthilkumar Chelladurai","doi":"10.2174/0113892002339055241211050131","DOIUrl":"https://doi.org/10.2174/0113892002339055241211050131","url":null,"abstract":"<p><p>Gene silencing is the characteristic that inhibits gene expression afforded by siRNA interference. The efficacy of the delivery system in terms of precision, efficacy, and stability can be enhanced by genebased drug delivery options. The delivery challenges and their associated side effects create a challenge for the delivery of gene-based drug delivery carriers. Nano-based delivery systems were reported to improve the efficacy of therapy. The absence of an efficient delivery mechanism that shields siRNA from nuclease degradation delivers it to cancer cells, and releases it into the cytoplasm of specific cancer cells without causing side effects is currently the greatest obstacle to the practical implementation of siRNA therapy. This article focuses on general aspects of siRNA and various siRNA nanocarrier-based formulations. In the near future, we will move towards the siRNA-based drug delivery approach.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Imatinib and Tacrolimus in Rats.","authors":"Naling Fan, Teng Guo, Liying Du, Mingfeng Liu, Xinran Chen","doi":"10.2174/0113892002319356241210073350","DOIUrl":"https://doi.org/10.2174/0113892002319356241210073350","url":null,"abstract":"<p><strong>Objective: </strong>Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats.</p><p><strong>Methods: </strong>Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and Ndesmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and Cmax of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and Cmax of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC0-24 and AUC0-∞ of tacrolimus (P < 0.05).</p><p><strong>Conclusion: </strong>Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing Pharmacokinetic Variability of Topiroxostat in Chinese Population: Insights from a Phase I Randomized Clinical Trial.","authors":"Tianqi Zhong, Kaizong Huang, LuYao Han, Wenbo Pang, Yan Xia, Shengjun Qu, Guo Yu, Yangsheng Chen, Hongwei Fan","doi":"10.2174/0113892002348045241210071452","DOIUrl":"https://doi.org/10.2174/0113892002348045241210071452","url":null,"abstract":"<p><strong>Objective: </strong>This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects.</p><p><strong>Methods: </strong>The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition.</p><p><strong>Results: </strong>Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79-0.98 h) than in males (0.53-0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h.</p><p><strong>Conclusion: </strong>The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies.","authors":"Yuting Yan, Yujiao Guo, Ziyi Wang, Wei He, Yu Zhu, Xiaoli Zhao, Luning Sun, Yongqing Wang","doi":"10.2174/0113892002338926241114080504","DOIUrl":"https://doi.org/10.2174/0113892002338926241114080504","url":null,"abstract":"<p><p>Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}