Drug Metabolism and Pharmacokinetics最新文献

Future direction of animal alternative/microphysiological systems in drug discovery and development

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-03-08 DOI: 10.1016/j.dmpk.2025.101479

Hiroshi Arakawa , Kazuo Takayama

引用次数: 0

Functional assessment of immortalized human brain microvascular endothelial cells with different passage numbers: A case study for a prospective proposal on variability management of in vitro blood-brain barrier models

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-20 DOI: 10.1016/j.dmpk.2025.101058

Seiya Ohki , Mei Fukuda , Tomoyo Baba , Naomi Wakayama , Hanae Morio , Shingo Ito , Sumio Ohtsuki , Yoshiyuki Yamaura , Takafumi Komori , Tomomi Furihata

{"title":"Functional assessment of immortalized human brain microvascular endothelial cells with different passage numbers: A case study for a prospective proposal on variability management of in vitro blood-brain barrier models","authors":"Seiya Ohki , Mei Fukuda , Tomoyo Baba , Naomi Wakayama , Hanae Morio , Shingo Ito , Sumio Ohtsuki , Yoshiyuki Yamaura , Takafumi Komori , Tomomi Furihata","doi":"10.1016/j.dmpk.2025.101058","DOIUrl":"10.1016/j.dmpk.2025.101058","url":null,"abstract":"<div><div><em>In vitro</em> blood-brain barrier (BBB) models, primarily consisting of brain microvascular endothelial cells (BMEC), are expected to play pivotal roles in evaluating drug permeability into the brain. However, these models often exhibit functional variability due to various factors, raising practical concerns that can hinder their use in drug development studies. By investigating cell passage numbers as one such factor, we aim to assess how BBB model functionality is affected and to propose a practical strategy for managing this variability. In transwell-BBB models - but not in spheroidal-BBB models - the intercellular barrier integrity was somewhat compromised when higher-passage human immortalized BMEC (HBMEC/ci18) were used. Nonetheless, a clear <em>in vitro-in vivo</em> correlation (IVIVC) curve could still be obtained with these transwell-BBB models, similar to those with lower passage number HBMEC/ci18, presumably allowing for reasonable estimation of <em>in vivo</em> drug permeability. Therefore, changes in functional levels of BBB models do not always significantly diminish their practical value in drug BBB permeability studies. Additionally, the IVIVC curve integrity may serve as an indicator for assessing acceptable BBB model functionality. These findings provide valuable insights for the future application of <em>in vitro</em> human BBB models in drug development studies.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101058"},"PeriodicalIF":2.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760690","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 pharmacokinetics of brexpiprazole in Japanese healthy subjects and patients with schizophrenia

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-11 DOI: 10.1016/j.dmpk.2025.101057

Koushi Higashi , Tomohiro Sasaki , Kazuo Aoki , Daisuke Sekine , Kenji Maeda , Yuki Shiomi , Yosuke Kawai

{"title":"Population pharmacokinetics of brexpiprazole in Japanese healthy subjects and patients with schizophrenia","authors":"Koushi Higashi , Tomohiro Sasaki , Kazuo Aoki , Daisuke Sekine , Kenji Maeda , Yuki Shiomi , Yosuke Kawai","doi":"10.1016/j.dmpk.2025.101057","DOIUrl":"10.1016/j.dmpk.2025.101057","url":null,"abstract":"<div><div>Brexpiprazole, widely approved for the treatment of schizophrenia, is an atypical antipsychotic that modulates serotonin–dopamine activity. To better understand the pharmacokinetics (PK) of brexpiprazole in Japanese patients, a population PK model was constructed and used to estimate steady state PK profiles and parameters as well as dopamine D<sub>2</sub>/D<sub>3</sub> receptor occupancy profiles after repeated oral administrations of brexpiprazole at 1 and 2 mg/day. Nonlinear mixed effects modelling was used to analyse data from a total of 398 healthy subjects and patients with schizophrenia who received brexpiprazole in three Japanese clinical trials. The PK of brexpiprazole were well described by a two-compartment disposition model with transit absorption compartments. Estimated glomerular filtration rate, age and cytochrome P450 2D6 phenotype were identified as significant covariates on CL/F only. The model predicted that, at a dose of 2 mg/day, trough plasma concentration (90 % prediction interval) of brexpiprazole is 77.1 (22.4–173) ng/mL and that dopamine D<sub>2</sub>/D<sub>3</sub> receptor occupancy is >80 % over one day for most patients at steady state. This suggests the recommended maintenance dose of 2 mg/day of brexpiprazole leads to clinically useful dopamine D<sub>2</sub>/D<sub>3</sub> receptor occupancy at steady state in Japanese patients.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101057"},"PeriodicalIF":2.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725461","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

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

Advanced in vitro evaluation of drug-induced kidney injury using microphysiological systems in drug discovery and development

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-02-03 DOI: 10.1016/j.dmpk.2025.101056

Hiroshi Arakawa , Kohei Matsushita , Naoki Ishiguro

{"title":"Advanced in vitro evaluation of drug-induced kidney injury using microphysiological systems in drug discovery and development","authors":"Hiroshi Arakawa , Kohei Matsushita , Naoki Ishiguro","doi":"10.1016/j.dmpk.2025.101056","DOIUrl":"10.1016/j.dmpk.2025.101056","url":null,"abstract":"<div><div>Drug-induced kidney injury (DIKI) is a major cause of acute kidney injury (AKI). Given concerns about animal welfare and the need for more accurate prediction of human events, there is an urgent need to develop an <em>in vitro</em> evaluation method for DIKI using human cells. Renal proximal tubular epithelial cells (RPTECs) are the main targets of DIKI in drug discovery and development because of their abundant expression of drug transporters that contribute to renal-specific drug distribution. In general, physiological kidney function is significantly reduced in primary cell monolayer culture systems. However, with recent advances in cell engineering and regenerative medicine, human kidney-derived cell culture systems, with higher kidney function compared to conventional systems, have been established. For example, three-dimensional cultured RPTECs show enhanced expression of drug transporters and higher predictive performance than monolayer culture systems. The use of organs-on-a-chip with liver and kidney co-cultures also allows the detection of drug metabolite-induced nephrotoxicity. Kidney organoids differentiated from induced pluripotent stem cells (iPS) have also been established. In this review, we introduce a recently established renal cell culture system that includes a microphysiological system, and review the <em>in vitro</em> methods used to evaluate DIKI in RPTECs.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"61 ","pages":"Article 101056"},"PeriodicalIF":2.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620887","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