Drug Metabolism and Pharmacokinetics最新文献

Micro-physiological system of human lung: The current status and application to drug discovery.

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-01-09 DOI: 10.1016/j.dmpk.2024.101050

Naoyuki Sone, Shimpei Gotoh

{"title":"Micro-physiological system of human lung: The current status and application to drug discovery.","authors":"Naoyuki Sone, Shimpei Gotoh","doi":"10.1016/j.dmpk.2024.101050","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101050","url":null,"abstract":"Various attempts have been made to elucidate the mechanisms of human lung development, its physiological functions, and diseases, in the hope of new drug discovery. Recent technological advancements in experimental animals, cell culture, gene editing, and analytical methods have provided new insights and therapeutic strategies. However, the results obtained from animal experiments are often inconsistent with those obtained from human data because of reproducibility issues caused by structural and physiological differences between mice and humans. In addition, it is not possible to accurately reproduce the internal environment of the human lung structure using conventional two-dimensional (2D) or three-dimensional (3D) cell culture methods. As a result, the micro-physiological system (MPS) technology, such as \"lung-on-a-chip\" that can culture human cells in a state close to human body environment have been developed, and its applications to disease models, toxicological studies, and drug discovery are accelerated worldwide. Here, we focus on the mimetics of the lung, including \"lung-on-a-chip\" technology, and review their recent progress, achievements and challenges. Finally, we discuss the role of these chips in drug discovery for refractory lung diseases.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101050"},"PeriodicalIF":2.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028202","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

Development and application of 3D cardiac tissues derived from human pluripotent stem cells.

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-01-04 DOI: 10.1016/j.dmpk.2024.101049

Masatoshi Ohno, Hidenori Tani, Shugo Tohyama

{"title":"Development and application of 3D cardiac tissues derived from human pluripotent stem cells.","authors":"Masatoshi Ohno, Hidenori Tani, Shugo Tohyama","doi":"10.1016/j.dmpk.2024.101049","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101049","url":null,"abstract":"Recently human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have become an attractive platform to evaluate drug responses for cardiotoxicity testing and disease modeling. Moreover, three-dimensional (3D) cardiac models, such as engineered heart tissues (EHTs) developed by bioengineering approaches, and cardiac spheroids (CSs) formed by spherical aggregation of hPSC-CMs, have been established as useful tools for drug discovery and transplantation. These 3D models overcome many of the shortcomings of conventional 2D hPSC-CMs, such as immaturity of the cells. Cardiac organoids (COs), like other organs, have also been studied to reproduce structures that resemble a heart in vivo more closely and optimize various culture conditions. Heart-on-a-chip (HoC) developed by a microfluidic chip-based technology that enables real-time monitoring of contraction and electrical activity, provides multifaceted information that is essential for capturing natural tissue development in vivo. Recently, 3D experimental systems have been developed to study organ interactions in vitro. This review aims to discuss the developments and advancements of hPSC-CMs and 3D cardiac tissues.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101049"},"PeriodicalIF":2.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028192","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

Advancements in Microphysiological systems: Exploring organoids and organ-on-a-chip technologies in drug development -focus on pharmacokinetics related organs.

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-12-17 DOI: 10.1016/j.dmpk.2024.101046

Hiroshi Kimura, Masaki Nishikawa, Naokata Kutsuzawa, Fumiya Tokito, Takuma Kobayashi, Dhimas Agung Kurniawan, Hiroki Shioda, Wenxin Cao, Kenta Shinha, Hiroko Nakamura, Kotaro Doi, Yasuyuki Sakai

{"title":"Advancements in Microphysiological systems: Exploring organoids and organ-on-a-chip technologies in drug development -focus on pharmacokinetics related organs.","authors":"Hiroshi Kimura, Masaki Nishikawa, Naokata Kutsuzawa, Fumiya Tokito, Takuma Kobayashi, Dhimas Agung Kurniawan, Hiroki Shioda, Wenxin Cao, Kenta Shinha, Hiroko Nakamura, Kotaro Doi, Yasuyuki Sakai","doi":"10.1016/j.dmpk.2024.101046","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101046","url":null,"abstract":"This study explored the evolving landscape of Microphysiological Systems (MPS), with a focus on organoids and organ-on-a-chip (OoC) technologies, which are promising alternatives to animal testing in drug discovery. MPS technology offers in vitro models with high physiological relevance, simulating organ function for pharmacokinetic studies. Organoids composed of 3D cell aggregates and OoCs mimicking in vivo environments based on microfluidic platforms represent the forefront of MPS. This paper provides a comprehensive overview of their application in studying the gut, liver, and kidney and their challenges in becoming reliable alternatives to in vivo models. Although MPS technology is not yet fully comparable to in vivo systems, its continued development, aided by in silico, automation, and AI approaches, is anticipated to bring about further advancements. Collaboration across multiple disciplines and ongoing regulatory discussions will be crucial in driving MPS toward practical and ethical applications in biomedical research and drug development.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101046"},"PeriodicalIF":2.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028106","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

Global expansion of microphysiological systems (MPS) and Japan's initiatives: Innovation in pharmaceutical development and path to regulatory acceptance.

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-12-17 DOI: 10.1016/j.dmpk.2024.101047

Daiju Yamazaki, Seiichi Ishida

{"title":"Global expansion of microphysiological systems (MPS) and Japan's initiatives: Innovation in pharmaceutical development and path to regulatory acceptance.","authors":"Daiju Yamazaki, Seiichi Ishida","doi":"10.1016/j.dmpk.2024.101047","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101047","url":null,"abstract":"Microphysiological systems (MPS) are gaining global attention as potential game-changers in pharmaceutical development. Since 2013, MPS suppliers from university laboratories in the United States and Europe have competed to develop these devices. After the development phase, the focus shifted to the accumulation of applications using MPS for pharmaceutical companies and end users. In Japan, the AMED-MPS project was launched in 2017, and since then, several MPS devices have been marketed by project participated suppliers. Initially, while Japanese pharmaceutical companies adopted foreign products, they also exhibited interest in domestically produced MPS devices. The utilization of new approach methodologies, including MPS, is expanding in the field of chemical substances risk assessment, and the Organization for Economic Co-operation and Development test guidelines are expected to adopt in vitro evaluation systems as alternatives to animal testing. This publication reviews global and Japanese trends surrounding MPS and outlines activities aimed at the regulatory acceptance of MPS as evaluation systems for medical drugs and chemicals.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101047"},"PeriodicalIF":2.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028109","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

Development of intestinal organoids and microphysiological systems and their application to drug discovery.

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-12-12 DOI: 10.1016/j.dmpk.2024.101045

Takahiro Iwao, Tamihide Matsunaga

{"title":"Development of intestinal organoids and microphysiological systems and their application to drug discovery.","authors":"Takahiro Iwao, Tamihide Matsunaga","doi":"10.1016/j.dmpk.2024.101045","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101045","url":null,"abstract":"The intestines are an important organ with a variety of functions. For drug discovery research, experimental animals and Caco-2 cells derived from a human colon carcinoma may be used to evaluate the absorption and safety of orally administered drugs. These systems have issues, such as species differences with humans in experimental animals, variations in gene expression patterns, very low drug-metabolizing activities in Caco-2 cells, and the recent trend toward reduced animal testing. Thus, there is a need for new evaluation systems. Intestinal organoid technology and microphysiological systems (MPS) have attracted attention as novel evaluation systems for predicting drug disposition, safety, and efficacy in humans in vitro. Intestinal organoids are three-dimensional structures that contain a variety of intestinal cells. They also contain crypt-villus structures similar to those of living bodies. Using MPS, it is possible to improve the functionality of cells and evaluate the linkage and crosstalk between the intestine and the liver. These systems are expected to be powerful tools for drug discovery research to predict efficacy and toxicity in humans. This review outlines the current status of intestinal organoids and MPS studies.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101045"},"PeriodicalIF":2.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028108","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

Corrigendum to "Establishment of human intestinal organoids derived from commercially available cryopreserved intestinal epithelium and evaluation for pharmacokinetic study" [Drug Metabol Pharmacokinet 53 (2024) 100532]. 对 "从市售低温保存的肠上皮细胞中提取的人体肠器官组织的建立和药代动力学研究评估"[Drug Metabol Pharmacokinet 53 (2024) 100532]的更正。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-12-01 Epub Date: 2024-11-16 DOI: 10.1016/j.dmpk.2024.101042

Kentaro Okada, Jumpei Yokota, Tomoki Yamashita, Tatsuya Inui, Wataru Kishimoto, Hiroshi Nakase, Hiroyuki Mizuguchi

引用次数: 0

Population pharmacokinetics of blonanserin in Japanese adolescent and adult patients with schizophrenia. blonanserin在日本青少年和成人精神分裂症患者中的群体药代动力学。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-11-28 DOI: 10.1016/j.dmpk.2024.101043

Daisuke Nemoto, Takeshi Takagaki, Atsushi Kitamura, Yoshiko Tomita

{"title":"Population pharmacokinetics of blonanserin in Japanese adolescent and adult patients with schizophrenia.","authors":"Daisuke Nemoto, Takeshi Takagaki, Atsushi Kitamura, Yoshiko Tomita","doi":"10.1016/j.dmpk.2024.101043","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101043","url":null,"abstract":"The second-generation antipsychotic blonanserin is a highly selective, full antagonist of dopamine D2 and D3 and serotonin 5-HT2A receptors. It is currently prescribed for patients with schizophrenia in Japan. We aimed to develop a population pharmacokinetic model of oral blonanserin, including data from 12 to 77 years old patients, to assess the covariates that influence blonanserin pharmacokinetics and evaluate appropriate dosage regimens in adolescents versus adults. The population pharmacokinetic analysis was conducted using plasma concentrations in 132 Japanese adolescent and 135 adult patients with schizophrenia (including 20 older adults [≥65 years] patients), and 49 healthy adults. The blonanserin population pharmacokinetics was described using a two-compartment model with first-order absorption with lag time. Relative bioavailability decreased in fasted conditions and with concomitant CYP3A4 inducer use. Apparent clearance in older adult was lower than adult and adolescent. Simulation revealed similar plasma exposures between adolescents and adults and slightly larger in older adults. Bayesian estimates of apparent clearance suggested no effects of age in adolescents between 12 and 18 years old. Together, these results reveal the pharmacokinetic characteristics of blonanserin over a wide age range and support the appropriateness of the approved dosing regimen for adolescent patients with schizophrenia in Japan.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101043"},"PeriodicalIF":2.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946461","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

The refined CYP2B6-Template system for studies of its ligand metabolisms. 改良的cyp2b6 -模板系统用于其配体代谢的研究。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-11-16 DOI: 10.1016/j.dmpk.2024.101037

Yasushi Yamazoe, Kouichi Yoshinari

{"title":"The refined CYP2B6-Template system for studies of its ligand metabolisms.","authors":"Yasushi Yamazoe, Kouichi Yoshinari","doi":"10.1016/j.dmpk.2024.101037","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101037","url":null,"abstract":"The previously reported Template system for the prediction of human CYP2B6-mediated reactions (Drug Metab Pharmacokinet 26 309-330, 2011) has been refined with the introduction of ideas of allowable width, Trigger-residue and the residue-initiated movement of ligands in the active site. The refined system also includes ideas of bi-molecule binding on Template. With the use of these ideas in common with other Template systems for human CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, and CYP3A4, 360 reactions of 261 distinct chemicals reported as CYP2B6 ligands were examined in the refined system. From their placements on the refined Template and rules for interaction modes, verifications of good and poor substrates, regio- and stereo-selectivities, and inhibitory interaction became faithfully available for these ligands, in which all the chemicals tested in the previous study were included. From the comparison of substrate specificities of human CYP2B6 and rat CYP2B1, size differences of one of the enzyme residues, Shelf, were suggested as a cause of their distinct catalyses. The refined CYP2B6-Template system will thus offer more reliable estimations of this human CYP catalyses toward ligands of diverse structures, together with their deciphering information to lead to judgments of metabolisms.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101037"},"PeriodicalIF":2.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964271","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

Population pharmacokinetic and exposure-response analysis to support a dosing regimen of CPX-351 (NS-87) in Japanese adult and pediatric patients with untreated high-risk acute myeloid leukemia. 人群药代动力学和暴露反应分析支持CPX-351 （NS-87）在日本成人和儿童未经治疗的高危急性髓性白血病患者中的给药方案。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-11-16 DOI: 10.1016/j.dmpk.2024.101038

Shunji Imai, Ayane Kitada, Aya Ogura, Michiyo Akagi, Mayumi Hasegawa, Grygoriy Vasilinin, J F Marier, Qi Wang, Tomohiko Ichikawa, Kazutomi Kusano

{"title":"Population pharmacokinetic and exposure-response analysis to support a dosing regimen of CPX-351 (NS-87) in Japanese adult and pediatric patients with untreated high-risk acute myeloid leukemia.","authors":"Shunji Imai, Ayane Kitada, Aya Ogura, Michiyo Akagi, Mayumi Hasegawa, Grygoriy Vasilinin, J F Marier, Qi Wang, Tomohiko Ichikawa, Kazutomi Kusano","doi":"10.1016/j.dmpk.2024.101038","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101038","url":null,"abstract":"CPX-351 (NS-87; Vyxeos®) has a characteristic liposomal formulation and contains cytarabine and daunorubicin at a 5:1 molar ratio, which demonstrates synergistic activity in both in vitro and in vivo animal models. It has been approved in several countries for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Since there are very few Asian patients, especially Japanese adult and pediatric patients, only a small clinical study has been conducted in Japanese adult patients and no study in Japanese pediatric patients. Therefore, we need to continue collecting data to ensure efficacy, especially in Japan. The objectives of this study were to evaluate the exposure and efficacy of CPX-351 in adult and pediatric Japanese patients. For these purposes, population pharmacokinetic and exposure-response analysis was conducted based on the established model/analysis using non-Japanese data by incorporating the newly obtained results of a Japanese clinical trial. No significant differences in pharmacokinetic exposure and efficacy were observed between non-Japanese adult patients and Japanese adult or pediatric patients. This information supports CPX-351 as a treatment option for untreated Japanese t-AML/AML-MRC patients on the basis of efficacy and safety when referred to the evidence from non-Japanese subjects.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101038"},"PeriodicalIF":2.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892966","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

In vitro hydrolysis of areca nut xenobiotics in human liver. 槟榔异种制剂在人肝脏中的体外水解研究。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2024-11-15 DOI: 10.1016/j.dmpk.2024.101039

Vincenzo Paolillo, Mahendran Jayakumar, Colton Sheperd, Andrew Tran, Stephanie Hoang, Nhu Dao, Parag Jain, Alan L Myers

{"title":"In vitro hydrolysis of areca nut xenobiotics in human liver.","authors":"Vincenzo Paolillo, Mahendran Jayakumar, Colton Sheperd, Andrew Tran, Stephanie Hoang, Nhu Dao, Parag Jain, Alan L Myers","doi":"10.1016/j.dmpk.2024.101039","DOIUrl":"https://doi.org/10.1016/j.dmpk.2024.101039","url":null,"abstract":"Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with good sensitivity, accuracy, and precision. Kinetics of arecoline and guvacoline hydrolysis best followed the Michaelis-Menten model. Apparent intrinsic clearance (Clint.in vivo) of arecoline was 57.8 ml/min/kg in HLM and 11.6 mL/min/kg in HLC, a 5-fold difference. Unexpectedly, guvacoline was dramatically less hydrolyzed than arecoline in both HLM and HLC, with Clint.in vivo estimates of 0.654 ml/min/kg and 0.466 ml/min/kg, respectively. These results demonstrate, for the first time, arecoline undergoes significant hydrolysis with high clearance rates in the liver. Furthermore, differential tissue metabolic rates and utilization of specific esterase inhibitors unequivocally demonstrated arecoline is a substrate for CES1 and not CES2.","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"101039"},"PeriodicalIF":2.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817247","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