Drug Metabolism and Pharmacokinetics最新文献

Comprehensive in vitro evaluation of the inhibitory effects of relatively high molecular weight peptides on drug-drug interaction-associated four liver transporters and its association with physicochemical properties

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-03 DOI: 10.1016/j.dmpk.2025.101055

Rika Ishikawa , Takashi Misawa , Yosuke Demizu , Yoshiro Saito , Ruri Kikura-Hanajiri , Kosuke Saito

{"title":"Comprehensive in vitro evaluation of the inhibitory effects of relatively high molecular weight peptides on drug-drug interaction-associated four liver transporters and its association with physicochemical properties","authors":"Rika Ishikawa , Takashi Misawa , Yosuke Demizu , Yoshiro Saito , Ruri Kikura-Hanajiri , Kosuke Saito","doi":"10.1016/j.dmpk.2025.101055","DOIUrl":"10.1016/j.dmpk.2025.101055","url":null,"abstract":"<div><div>In recent years, advances in peptide synthesis have enabled the construction of relatively high molecular weight (Mw; >1 kDa) peptides using various types of amino acids (AAs), including proteinogenic/natural and nonnatural AAs. This advancement helps in obtaining peptides with improved stability, cell membrane permeability, and/or target-binding affinity. However, drug-drug interaction (DDI) information for these peptides remains scarce. Therefore, we focused on relatively high Mw peptides to examine their potential in inhibiting liver transporters, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and breast cancer resistant protein (BCRP) <em>in vitro</em>. We addressed the inhibitory effects of various types of cyclic peptides containing non-natural AAs and cell-penetrating peptides composed of proteinogenic/natural AAs. Our results demonstrated that several peptides inhibited transport activities, indicating that they can potentially cause DDI. We further evaluated the relationship between their inhibition potency and physicochemical properties (Mw and hydrophobicity or charge of the constituting AA) to characterize the specific physicochemical properties contributing to their inhibition potency. The hydrophobic AA contents of the peptides correlated with the inhibition potencies for all four transporters. Our findings demonstrate the transporter-mediated DDI potential of peptides and the necessity of their evaluation for drug development.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"61 ","pages":"Article 101055"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549901","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

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 : 2025-02-01 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":"10.1016/j.dmpk.2024.101043","url":null,"abstract":"<div><div>The second-generation antipsychotic blonanserin is a highly selective, full antagonist of dopamine D<sub>2</sub> and D<sub>3</sub> and serotonin 5-HT<sub>2A</sub> 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.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101043"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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

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 : 2025-02-01 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":"10.1016/j.dmpk.2024.101046","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101046"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Appreciation to Reviewers

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-01 DOI: 10.1016/S1347-4367(25)00003-5

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 : 2025-02-01 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":"10.1016/j.dmpk.2024.101049","url":null,"abstract":"<div><div>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 <em>in vivo</em> 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 <em>in vivo</em>. Recently, 3D experimental systems have been developed to study organ interactions <em>in vitro</em>. This review aims to discuss the developments and advancements of hPSC-CMs and 3D cardiac tissues.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101049"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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":"OA","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 : 2025-02-01 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":"10.1016/j.dmpk.2024.101047","url":null,"abstract":"<div><div>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 <em>in vitro</em> 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.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101047"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of obesity on pharmacokinetics of transdermal fentanyl: Single-center retrospective study and animal study 肥胖对芬太尼透皮药代动力学的影响：单中心回顾性研究和动物研究。

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101035

Satoshi Mizuno , Shintaro Gake , Makiko Takabayashi , Yuriko Ito , Hiroko Sanada , Natsumi Sugimoto , Akari Maeda , Takuto Tamamura , Kazuki Sawamoto , Yusuke Hara , Yoshiko Ohi , Chiaki Tsuji , Yukiko Shiomoto , Yukio Kato , Arimi Fujita , Tsutomu Shimada , Ken-ichi Miyamoto , Yoshimichi Sai

{"title":"Effect of obesity on pharmacokinetics of transdermal fentanyl: Single-center retrospective study and animal study","authors":"Satoshi Mizuno , Shintaro Gake , Makiko Takabayashi , Yuriko Ito , Hiroko Sanada , Natsumi Sugimoto , Akari Maeda , Takuto Tamamura , Kazuki Sawamoto , Yusuke Hara , Yoshiko Ohi , Chiaki Tsuji , Yukiko Shiomoto , Yukio Kato , Arimi Fujita , Tsutomu Shimada , Ken-ichi Miyamoto , Yoshimichi Sai","doi":"10.1016/j.dmpk.2024.101035","DOIUrl":"10.1016/j.dmpk.2024.101035","url":null,"abstract":"<div><div>A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI ≥25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5–25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (<em>fa</em>/<em>fa</em>) rats as an obese model and Zucker (<em>+</em>/<em>+</em>) rats as a control. No difference in systemic clearance (<em>CL</em><sub>tot</sub>) after intravenous administration was observed between the two groups. However, transdermal bioavailability (<em>F</em>) and fentanyl release ratio from the formulation (<em>F</em><sub>a</sub>) were significantly increased in Zucker (<em>fa</em>/<em>fa</em>) rats compared to Zucker (<em>+</em>/<em>+</em>) rats. Skin availability (<em>F</em><sub>skin</sub>), calculated as <em>F</em> divided by <em>F</em><sub>a</sub>, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101035"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853519","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

Human brain organoids for understanding substance use disorders 用于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 : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101036

Kangle Li , Longjun Gu , Hongwei Cai , Hui-Chen Lu , Ken Mackie , Feng Guo

{"title":"Human brain organoids for understanding substance use disorders","authors":"Kangle Li , Longjun Gu , Hongwei Cai , Hui-Chen Lu , Ken Mackie , Feng Guo","doi":"10.1016/j.dmpk.2024.101036","DOIUrl":"10.1016/j.dmpk.2024.101036","url":null,"abstract":"<div><div>Substance use disorders (SUDs) are complex mental health conditions involving a problematic pattern of substance use. Challenges remain in understanding its neural mechanisms, which are likely to lead to improved SUD treatments. Human brain organoids, brain-like 3D in vitro cultures derived from human stem cells, show unique potential in recapitulating the response of a developing human brain to substances. Here, we review the recent progress in understanding SUD using human brain organoid models focusing on neurodevelopmental perspectives. We first summarize the background of SUD in humans. Moreover, we introduce the development of various human brain organoid models and then discuss current progress and findings underlying the abuse of substances like nicotine, alcohol, and other addictive drugs using organoid models. Furthermore, we review efforts to develop organ chips and microphysiological systems to engineer better human brain organoids for advancing SUD studies. Lastly, we conclude by elaborating on the current challenges and future directions of SUD studies using human brain organoids.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101036"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681198","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 : 2025-02-01 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":"10.1016/j.dmpk.2024.101037","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"60 ","pages":"Article 101037"},"PeriodicalIF":2.7,"publicationDate":"2025-02-01","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

Opportunities for microphysiological systems from the view of Japanese industries

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101034

Hitoshi Naraoka, Takuma Iguchi, Kosuke Harada, Toru Usui, Yoshiaki Suwa, Masamitsu Ando, Takeshi Sakura, Tomoki Ohkubo

引用次数: 0