Drug Metabolism and Pharmacokinetics最新文献

Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling. 利用基于生理学的药代动力学模型了解voclosporin的负食物效应机制。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-09-10 DOI: 10.1016/j.dmpk.2024.101032

Ayahisa Watanabe, Takanori Akazawa, Motohiro Fujiu

{"title":"Understanding mechanisms of negative food effect for voclosporin using physiologically based pharmacokinetic modeling.","authors":"Ayahisa Watanabe, Takanori Akazawa, Motohiro Fujiu","doi":"10.1016/j.dmpk.2024.101032","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101032","url":null,"abstract":"Negative food effect refers to a reduction in bioavailability, when a drug is taken with food. Voclosporin, a highly lipophilic cyclic peptide drug for treatment of active lupus nephritis, has shown negative food effect in clinical trials. Here, the cause of the negative food effect of voclosporin was investigated using physiologically based pharmacokinetic (PBPK) modeling to understand the mechanism responsible for oral absorption of voclosporin. Voclosporin is a substrate for P-glycoprotein and CYP3A4, and it has been evaluated for intestinal membrane permeability in human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs). The membrane permeability in hiPSC-IECs is integrated into the PBPK model for simulating permeability accurately. The PBPK model simulated the systemic PK profile in fasted state in human. Then, the PBPK model with in vitro adsorption of voclosporin onto food simulated the systemic PK profile in fed state for food effect. In addition, the PBPK model for rats also simulated the plasma profile of voclosporin for the food effect. These results suggest that a possible cause of the negative food effect of voclosporin is the adsorption of voclosporin to food in gastrointestinal tract. These approaches could facilitate understanding of the mechanisms responsible for oral absorption of cyclic peptides.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460449","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}

引用次数: 0

Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice 定量预测临床实践中 CYP3A 诱导的药物间相互作用

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-08-01 DOI: 10.1016/j.dmpk.2024.101010

{"title":"Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice","authors":"","doi":"10.1016/j.dmpk.2024.101010","DOIUrl":"10.1016/j.dmpk.2024.101010","url":null,"abstract":"<div>There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and Cmax for drug candidates identified as a “victims” of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the AUC ratio (AUCR) of a few CYP3A substrates in the presence and absence of CYP3A inducers. In the present study, we investigate the predictability of AUCR and also Cmax ratio (CmaxR) in additional 54 clinical studies. The fraction metabolized by CYP3A (fm), the intestinal bioavailability (Fg), and the hepatic intrinsic clearance (CLint) of substrates were determined by the in vitro experiments as well as clinical data used for calculating AUCR and CmaxR. The result showed that 65–69% and 65–67% of predictions were within 2-fold of observed AUCR and CmaxR, respectively. A simulation using multiple parameter combinations suggested that the variability of fm and Fg within a certain range might have a minimal impact on the calculation output. These findings suggest that clinical AUCR and CmaxR of CYP3A substrates can be quantitatively predicted from the preclinical stage.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347436724000168/pdfft?md5=05af9e2101d932059de43ff8740db672&pid=1-s2.0-S1347436724000168-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140147294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic variation present in the CYP3A4 gene in Ni-Vanuatu and Kenyan populations in malaria endemicity 疟疾流行地区尼-瓦努阿图和肯尼亚人口中 CYP3A4 基因的遗传变异

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-08-01 DOI: 10.1016/j.dmpk.2024.101029

{"title":"Genetic variation present in the CYP3A4 gene in Ni-Vanuatu and Kenyan populations in malaria endemicity","authors":"","doi":"10.1016/j.dmpk.2024.101029","DOIUrl":"10.1016/j.dmpk.2024.101029","url":null,"abstract":"<div>Cytochrome P450 3A4 (CYP3A4) enzyme is involved in the metabolism of about 30 % of clinically used drugs, including the antimalarials artemether and lumefantrine. CYP3A4 polymorphisms yield enzymatic variants that contribute to inter-individual variation in drug metabolism. Here, we examined CYP3A4 polymorphisms in populations from malaria-endemic islands in Lake Victoria, Kenya, and Vanuatu, to expand on the limited data sets. We used archived dried blood spots collected from 142 Kenyan and 263 ni-Vanuatu adults during cross-sectional malaria surveys in 2013 and 2005–13, respectively, to detect CYP3A4 variation by polymerase chain reaction (PCR) and sequencing. In Kenya, we identified 14 CYP3A4 single nucleotide polymorphisms (SNPs), including the 4713G (CYP3A4∗1B; allele frequency 83.9 %) and 19382A (CYP3A4∗15; 0.7 %) variants that were previously linked to altered metabolism of antimalarials. In Vanuatu, we detected 15 SNPs, including the 4713A (CYP3A4∗1A; 88.6 %) and 25183C (CYP3A4∗18; 0.6 %) variants. Additionally, we detected a rare and novel SNP C4614T (0.8 %) in the 5′ untranslated region. A higher proportion of CYP3A4 genetic variance was found among ni-Vanuatu populations (16 %) than among Lake Victoria Kenyan populations (8 %). Our work augments the scarce data sets and contributes to improved precision medicine approaches, particularly to anti-malarial chemotherapy, in East African and Pacific Islander populations.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347436724000351/pdfft?md5=e58051588ccdc0e46f04f97fd0bf3ea1&pid=1-s2.0-S1347436724000351-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141843365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction 基于生理学的 CYP2C8 底物罗格列酮及其代谢物的药代动力学模型，以预测代谢药物与药物之间的相互作用。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-08-01 DOI: 10.1016/j.dmpk.2024.101023

{"title":"Physiologically based pharmacokinetic modeling of CYP2C8 substrate rosiglitazone and its metabolite to predict metabolic drug-drug interaction","authors":"","doi":"10.1016/j.dmpk.2024.101023","DOIUrl":"10.1016/j.dmpk.2024.101023","url":null,"abstract":"<div>Rosiglitazone is an activator of nuclear peroxisome proliferator-activated (PPAR) receptor gamma used in the treatment of type 2 diabetes mellitus. The elimination of rosiglitazone occurs mainly via metabolism, with major contribution by enzyme cytochrome P450 (CYP) 2C8. Primary routes of rosiglitazone metabolism are N-demethylation and hydroxylation. Modulation of CYP2C8 activity by co-administered drugs lead to prominent changes in the exposure of rosiglitazone and its metabolites. Here, we attempt to develop mechanistic parent-metabolite physiologically based pharmacokinetic (PBPK) model for rosiglitazone. Our goal is to predict potential drug-drug interaction (DDI) and consequent changes in metabolite N-desmethyl rosiglitazone exposure. The PBPK modeling was performed in the PKSim® software using clinical pharmacokinetics data from literature. The contribution to N-desmethyl rosiglitazone formation by CYP2C8 was delineated using vitro metabolite formation rates from recombinant enzyme system. Developed model was verified for prediction of rosiglitazone DDI potential and its metabolite exposure based on observed clinical DDI studies. Developed model exhibited good predictive performance both for rosiglitazone and N-desmethyl rosiglitazone respectively, evaluated based on commonly acceptable criteria. In conclusion, developed model helps with prediction of CYP2C8 DDI using rosiglitazone as a substrate, as well as changes in metabolite exposure. In vitro data for metabolite formation can be successfully utilized to translate to in vivo conditions.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874459","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}

引用次数: 0

Iminium ion metabolites are formed from nintedanib by human CYP3A4 人类 CYP3A4 可从 nintedanib 生成氨离子代谢物

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-08-01 DOI: 10.1016/j.dmpk.2024.101025

{"title":"Iminium ion metabolites are formed from nintedanib by human CYP3A4","authors":"","doi":"10.1016/j.dmpk.2024.101025","DOIUrl":"10.1016/j.dmpk.2024.101025","url":null,"abstract":"<div>Nintedanib is used to treat idiopathic pulmonary fibrosis, systemic sclerosis, interstitial lung disease, and progressive fibrotic interstitial lung disease. It is primarily cleared via hepatic metabolism, hydrolysis, and glucuronidation. In addition, formation of the iminium ion, a possible reactive metabolite, was predicted based on the chemical structure of nintedanib. To obtain a hint which may help to clarify the cause of nintedanib-induced liver injury, we investigated whether iminium ions were formed in the human liver. To detect unstable iminium ions using liquid chromatography-tandem mass spectrometry (LC-MS/MS), potassium cyanide was added to the reaction mixture as a trapping agent. Human liver and intestinal microsomes were incubated with nintedanib in the presence of NADPH to form two iminium ion metabolites on the piperazine ring. Their formation is strongly inhibited by ketoconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. Among the recombinant P450s, only CYP3A4 formed cyanide adducts. The role of CYP3A4 was supported by the positive correlation between CYP3A4 protein abundance, as determined by LC-MS-based proteomics, and the formation of cyanide adducts in 25 individual human liver microsomes. In conclusion, we have demonstrated that iminium ion metabolites are formed from nintedanib by CYP3A4 as potential reactive metabolites.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141396519","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}

引用次数: 0

Human brain organoids for understanding substance use disorders 了解药物使用障碍的人脑器官模型

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-07-26 DOI: 10.1016/j.dmpk.2024.101031

引用次数: 0

Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells 环去肽去甲芦荟素 E 在 HeLa 细胞中的膜转运、代谢和靶蛋白结合特性

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-07-02 DOI: 10.1016/j.dmpk.2024.101028

{"title":"Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells","authors":"","doi":"10.1016/j.dmpk.2024.101028","DOIUrl":"10.1016/j.dmpk.2024.101028","url":null,"abstract":"<div>Cyclic peptides have attracted attention as new modalities for drug development owing to their unique pharmacokinetic and pharmacodynamic properties. Destruxin E, a 19-membered cyclodepsipeptide, is a promising candidate drug for cancer therapy. The purpose of the present study was to clarify the molecular mechanisms underlying membrane transport, metabolism, and the binding for target molecules of destruxin E in human cervical carcinoma HeLa cells used as a model of cancer cells. The influx transport and the intracellular metabolism of destruxin E were non-saturable and saturable, respectively, at up to 10 μM. The intracellular amounts of destruxin E and destruxin E-diol after incubation of destruxin E with the cells significantly decreased at 4 °C compared to those at 37 °C. Destruxin E-diol, but not destruxin E, undergoes efflux transport out of cells via P-gp/MDR1/ABCB1 and BCRP/ABCG2. The epoxide hydrolase EPHX2 functions as a potent metabolizing enzyme that can convert the epoxide of destruxin E to the destruxin E-diol. Treatment with an EPHX2 inhibitor increased the intracellular destruxin E levels and enhanced the inhibitory activity of vacuolar type-H+ ATPase. These results suggest that epoxide hydrolase could be a regulatory factor for intracellular destruxin E levels and its pharmacological activity.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141693654","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}

引用次数: 0

Preface: In silico technologies to facilitate drug development 前言促进药物开发的硅学技术

IF 2.1 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-06-01 DOI: 10.1016/j.dmpk.2024.101022

Kazuya Maeda Ph.D., Masayo Oishi Ph.D.

引用次数: 0

Beyond the basics: A deep dive into parameter estimation for advanced PBPK and QSP models 超越基础：深入了解高级 PBPK 和 QSP 模型的参数估计

IF 2.1 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-06-01 DOI: 10.1016/j.dmpk.2024.101011

Kota Toshimoto

{"title":"Beyond the basics: A deep dive into parameter estimation for advanced PBPK and QSP models","authors":"Kota Toshimoto","doi":"10.1016/j.dmpk.2024.101011","DOIUrl":"10.1016/j.dmpk.2024.101011","url":null,"abstract":"<div>Physiologically-based pharmacokinetic (PBPK) models and quantitative systems pharmacology (QSP) models have contributed to drug development strategies. The parameters of these models are commonly estimated by capturing observed values using the nonlinear least-squares method. Software packages for PBPK and QSP modeling provide a range of parameter estimation algorithms. To choose the most appropriate method, modelers need to understand the basic concept of each approach. This review provides a general introduction to the key points of parameter estimation with a focus on the PBPK and QSP models, and the respective parameter estimation algorithms. The latter part assesses the performance of five parameter estimation algorithms – the quasi-Newton method, Nelder-Mead method, genetic algorithm, particle swarm optimization, and Cluster Gauss-Newton method – using three examples of PBPK and QSP modeling. The assessment revealed that some parameter estimation results were significantly influenced by the initial values. Moreover, the choice of algorithms demonstrating good estimation results heavily depends on factors such as model structure and the parameters to be estimated. To obtain credible parameter estimation results, it is advisable to conduct multiple rounds of parameter estimation under different conditions, employing various estimation algorithms.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S134743672400017X/pdfft?md5=df144f44a617f6c8d8e5f084a82d4f42&pid=1-s2.0-S134743672400017X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140405620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DMPK perspective on quantitative model analysis for chimeric antigen receptor cell therapy: Advances and challenges 从 DMPK 角度看嵌合抗原受体细胞疗法的定量模型分析：进展与挑战

IF 2.1 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-06-01 DOI: 10.1016/j.dmpk.2024.101003

Akihiko Goto, Yuu Moriya, Miyu Nakayama, Shinji Iwasaki, Syunsuke Yamamoto

{"title":"DMPK perspective on quantitative model analysis for chimeric antigen receptor cell therapy: Advances and challenges","authors":"Akihiko Goto, Yuu Moriya, Miyu Nakayama, Shinji Iwasaki, Syunsuke Yamamoto","doi":"10.1016/j.dmpk.2024.101003","DOIUrl":"10.1016/j.dmpk.2024.101003","url":null,"abstract":"<div>Chimeric antigen receptor (CAR) cells are genetically engineered immune cells that specifically target tumor-associated antigens and have revolutionized cancer treatment, particularly in hematological malignancies, with ongoing investigations into their potential applications in solid tumors. This review provides a comprehensive overview of the current status and challenges in drug metabolism and pharmacokinetics (DMPK) for CAR cell therapy, specifically emphasizing on quantitative modeling and simulation (M&S). Furthermore, the recent advances in quantitative model analysis have been reviewed, ranging from clinical data characterization to mechanism-based modeling that connects in vitro and in vivo nonclinical and clinical study data. Additionally, the future perspectives and areas for improvement in CAR cell therapy translation have been reviewed. This includes using formulation quality considerations, characterization of appropriate animal models, refinement of in vitro models for bottom-up approaches, and enhancement of quantitative bioanalytical methodology. Addressing these challenges within a DMPK framework is pivotal in facilitating the translation of CAR cell therapy, ultimately enhancing the patients’ lives through efficient CAR cell therapies.</div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347436724000090/pdfft?md5=fbce09f1734f25402898ac010f89ccf3&pid=1-s2.0-S1347436724000090-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139873153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0