Drug Metabolism and Pharmacokinetics最新文献

Exploring the effect of intracellular loop 1 genetic variants in human ABCG2 on transport activity and protein abundance 探讨人ABCG2细胞内环1遗传变异对转运活性和蛋白丰度的影响

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-03-15 DOI: 10.1016/j.dmpk.2025.101482

Noora Sjöstedt , Ritchie G.M. Timmermans , Marika Vieraankivi , Laura Suominen , Kati-Sisko Vellonen , Madhushree Bhattacharya , Seppo Auriola , Heidi Kidron

{"title":"Exploring the effect of intracellular loop 1 genetic variants in human ABCG2 on transport activity and protein abundance","authors":"Noora Sjöstedt , Ritchie G.M. Timmermans , Marika Vieraankivi , Laura Suominen , Kati-Sisko Vellonen , Madhushree Bhattacharya , Seppo Auriola , Heidi Kidron","doi":"10.1016/j.dmpk.2025.101482","DOIUrl":"10.1016/j.dmpk.2025.101482","url":null,"abstract":"<div><div>ABCG2 (breast cancer resistance protein, BCRP), can affect drug disposition, and thus, variation in the <em>ABCG2</em> gene may alter drug exposure. We studied non-synonymous naturally occurring single-nucleotide variants (SNVs) in intracellular loop 1 (ICL1), which contains a coupling helix that transmits conformational changes in the protein. Reference ABCG2, the common SNVs V12M and Q141K, and five SNVs (K453R, I456V, H457R, G462R and G462V) in ICL1 were expressed in HEK293 cells. Additionally, combinations of selected SNVs were expressed to determine if an activating substitution in ICL1 could compensate for an inactivating substitution elsewhere. Transport of Lucifer yellow, estrone sulfate and rosuvastatin was studied using membrane vesicles and the ABCG2 abundance was quantified. While K453R and I456V abundance was similar to the reference ABCG2, abundance was lower for H457R and G462R/V. Apparent transport activities were partially substrate dependent, but excluding G462R/V, the ICL variants transported at least one of the substrates similarly to the reference ABCG2. In double substitutions, I456V had a more consistent effect than H457R on both transport activity and protein abundance. Altogether, SNVs in ICL1 can have both detrimental and beneficial effects on ABCG2 activity. Effects may be hard to predict, especially if more than one SNV is present.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101482"},"PeriodicalIF":2.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791013","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

In vitro liver models for toxicological research 体外肝模型毒理学研究

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-03-13 DOI: 10.1016/j.dmpk.2025.101478

Ichiro Fukunaga , Takanori Takebe

{"title":"In vitro liver models for toxicological research","authors":"Ichiro Fukunaga , Takanori Takebe","doi":"10.1016/j.dmpk.2025.101478","DOIUrl":"10.1016/j.dmpk.2025.101478","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) presents a major challenge not only in new drug development but also in post-marketing withdrawals and the safety of food, cosmetics, and chemicals. Experimental model organisms such as the rodents have been widely used for preclinical toxicological testing. However, the tension exists associated with the ethical and sustainable use of animals in part because animals do not necessarily inform the human-specific ADME (adsorption, dynamics, metabolism and elimination) profiling. To establish alternative models in humans, in vitro hepatic tissue models have been proposed, ranging from primary hepatocytes, immortal hepatocytes, to the development of new cell resources such as stem cell-derived hepatocytes. Given the evolving number of novel alternative methods, understanding possible combinations of cell sources and culture methods will be crucial to develop the context-of-use assays. This review primarily focuses on 3D liver organoid models for conducting. We will review the relevant cell sources, bioengineering methods, selection of training compounds, and biomarkers towards the rationale design of in vitro toxicology testing.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101478"},"PeriodicalIF":2.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799927","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

Future direction of animal alternative/microphysiological systems in drug discovery and development 动物替代/微生理系统在药物发现和开发中的未来方向

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 不同传代数的永生化人脑微血管内皮细胞的功能评估：体外血脑屏障模型变异性管理前瞻性建议的案例研究

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 brexpiprazole在日本健康人及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 : 2025-02-11 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 体外综合评价相对高分子量肽对药物相互作用相关的四种肝脏转运蛋白的抑制作用及其与理化性质的关系

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 微生理系统在药物研发中对药物性肾损伤的体外评价研究进展

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