Drug Metabolism and Pharmacokinetics最新文献

英文中文

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 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101043

Daisuke Nemoto, Takeshi Takagaki, Atsushi Kitamura, Yoshiko Tomita

The second-generation antipsychotic blonanserin is a highly selective, full antagonist of dopamine D₂ and D₃ and serotonin 5-HT_2A 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.

第二代抗精神病药物blonanserin是一种高度选择性的多巴胺D2和D3以及5-HT2A受体的完全拮抗剂。目前在日本，这种药物被用于精神分裂症患者。我们旨在建立口服blonanserin的人群药代动力学模型，包括12至77岁患者的数据，以评估影响blonanserin药代动力学的协变量，并评估青少年与成人的适当剂量方案。对132名日本青少年和135名成年精神分裂症患者（包括20名老年人[≥65岁]患者）以及49名健康成年人的血浆浓度进行了人群药代动力学分析。用一阶吸收带滞后时间的双室模型描述了blonanserin群体药代动力学。在禁食和同时使用CYP3A4诱导剂的情况下，相对生物利用度下降。老年人的表观清除率低于成人和青少年。模拟显示，青少年和成年人的血浆暴露量相似，老年人的暴露量略大。贝叶斯估计的表观清除率表明，年龄对12至18岁的青少年没有影响。总之，这些结果揭示了blonanserin在广泛年龄范围内的药代动力学特征，并支持日本批准的青少年精神分裂症患者给药方案的适用性。

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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 Q2 PHARMACOLOGY & PHARMACY

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

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.

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引用次数: 0

Appreciation to Reviewers

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

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 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101049

Masatoshi Ohno , Hidenori Tani , Shugo Tohyama

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.

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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 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101047

Daiju Yamazaki , Seiichi Ishida

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.

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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 Q2 PHARMACOLOGY & PHARMACY

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

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 (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CL_tot) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (F_a) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (F_skin), calculated as F divided by F_a, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.

我们进行了一项回顾性研究和一项动物研究，以调查影响经皮芬太尼剂量的因素，以实现从其他阿片类药物切换的患者充分缓解疼痛。在回顾性研究中，患者因素包括性别、年龄、体重指数（BMI）和血清白蛋白浓度。在肥胖（BMI≥25）患者中，尽管初始剂量相同，经皮芬太尼滴药后剂量显著低于正常（BMI 18.5-25）患者。为了支持这一意想不到的发现，芬太尼被静脉注射和经皮给药给Zucker （fa/fa）大鼠作为肥胖模型，Zucker（+/+）大鼠作为对照。两组静脉给药后的全身清除率（CLtot）无差异。然而，与Zucker（+/+）大鼠相比，Zucker （Fa / Fa）大鼠的透皮生物利用度(F)和芬太尼释放比（Fa）显著增加。皮肤有效度（Fskin）（以F / Fa计算）也显著增加。这些结果表明，在芬太尼透皮剂量的滴定中应考虑肥胖因素。

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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 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101037

Yasushi Yamazoe , Kouichi Yoshinari

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.

先前报道的用于预测人类cyp2b6介导反应的模板系统（Drug Metab Pharmacokinet 26 309-330, 2011）随着允许宽度、触发残基和活性位点配体残基启动运动的概念的引入而得到完善。改进后的系统还包括双分子在模板上结合的思想。与其他人类CYP1A1、CYP1A2、CYP2C8、CYP2C9、CYP2C18、CYP2C19、CYP2E1和CYP3A4的模板系统一样，使用这些想法，在改进的系统中检测了261种不同化学物质作为CYP2B6配体的360次反应。从它们在精炼模板上的位置和相互作用模式的规则，这些配体的良好和不良底物，区域和立体选择性以及抑制相互作用的验证变得忠实地可用，其中包括先前研究中测试的所有化学物质。通过比较人CYP2B6和大鼠CYP2B1的底物特异性，其中一个酶残基Shelf的大小差异被认为是它们不同催化作用的原因。因此，改进的CYP2B6-Template系统将提供更可靠的估计这种人类CYP对不同结构配体的催化作用，以及它们的解码信息，从而判断代谢。

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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 Q2 PHARMACOLOGY & PHARMACY

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

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.

物质使用障碍（SUD）是一种复杂的精神疾病，涉及有问题的物质使用模式。在了解其神经机制方面仍存在挑战，而了解这些机制很可能有助于改进药物使用障碍的治疗。人脑器官组织是由人类干细胞衍生的类脑三维体外培养物，在重现发育中的人脑对药物的反应方面显示出独特的潜力。在此，我们从神经发育的角度回顾了利用人脑类器官模型了解 SUD 的最新进展。我们首先总结了人类 SUD 的背景。此外，我们还介绍了各种人脑类器官模型的发展，然后讨论了目前利用类器官模型研究尼古丁、酒精和其他成瘾药物滥用的进展和发现。此外，我们还回顾了开发器官芯片和微生理系统的工作，以设计出更好的人脑类器官，推动 SUD 研究。最后，我们阐述了使用人脑器官模型进行 SUD 研究的当前挑战和未来方向。

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引用次数: 0

Opportunities for microphysiological systems from the view of Japanese industries

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

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

Regulatory authorities and pharmaceutical companies in Europe and the United States have paid attention to microphysiological systems (MPS), and various consortia and academic societies have been established. They are actively working toward their implementation under individual company or regulatory acceptance. In Japan, some AMED projects, academic societies, and consortia have also been established and activities have begun. This article focuses on domestic and international trends regarding MPS, especially on Japanese industries related to MPS, and describes the current status, challenges, and prospects of Japanese pharmaceutical companies, CROs, Food company, and MPS-related product development companies including the results of a survey conducted by CSAHi-MPS, an industrial MPS consortium in Japan.

引用次数: 0

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

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-02-01 DOI: 10.1016/j.dmpk.2024.101050

Naoyuki Sone, Shimpei Gotoh

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.

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引用次数: 0

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