Drug Metabolism and Pharmacokinetics最新文献

PBPK Modeling Addresses Oral Absorption-Mediated Drug Interactions. PBPK模型解决了口服吸收介导的药物相互作用。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2026-01-27 DOI: 10.1016/j.dmpk.2026.101523

Xinyuan Zhang, Grace Fraczkiewicz, Viera Lukacova

Absorption is the first and imperative step to understanding the pharmacokinetics (PK) and ADME (absorption, distribution, metabolism, and excretion) of a drug product. Drug interactions also occur during the absorption process and have the potential to alter the PK of a drug, causing safety and efficacy concerns. Physiologically based pharmacokinetic (PBPK) modeling has emerged as a powerful tool to assess these interactions, supporting drug development and regulatory decisions. This review explores key mechanisms underlying oral absorption-mediated DDIs, including alterations in gastric pH, gastric emptying, gastrointestinal transit, and food effects. While interactions involving intestinal transporters and enzymes are reviewed in other articles of this special issue, this work emphasizes changes in gastrointestinal factors that influence drug absorption. Applications of PBPK modeling are illustrated through case examples predicting pH-dependent interactions, gastric transit alterations, and food effects. Regulatory acceptance of PBPK-based DDI assessments is discussed with reference to recent U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) case studies. Finally, future directions highlight the integration of machine learning and global harmonization of regulatory expectations. PBPK modeling offers a mechanistic approach for assessing absorption-mediated DDI risk, enhancing decision-making in drug development and regulatory science.

吸收是了解药物的药代动力学（PK）和ADME（吸收、分布、代谢和排泄）的第一步，也是必不可少的一步。药物相互作用也发生在吸收过程中，并有可能改变药物的PK，引起安全性和有效性问题。基于生理的药代动力学（PBPK）模型已经成为评估这些相互作用的有力工具，支持药物开发和监管决策。这篇综述探讨了口服吸收介导的ddi的关键机制，包括胃pH值的改变、胃排空、胃肠道转运和食物效应。虽然涉及肠道转运蛋白和酶的相互作用在本特刊的其他文章中进行了综述，但本工作强调影响药物吸收的胃肠道因素的变化。通过预测ph依赖性相互作用、胃转运改变和食物效应的案例，说明了PBPK模型的应用。参考最近美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）的案例研究，讨论了基于pbpp的DDI评估的监管接受程度。最后，未来的方向强调机器学习的整合和监管期望的全球协调。PBPK模型为评估吸收介导的DDI风险提供了一种机制方法，增强了药物开发和监管科学的决策。

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引用次数: 0

Integrating renal transporter biomarkers into drug development: Discovery, clinical assessment, and precision medicine. 将肾转运蛋白生物标志物整合到药物开发中：发现、临床评估和精准医学。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2026-01-09 DOI: 10.1016/j.dmpk.2026.101515

Sook Wah Yee, Bhagwat Prasad, Hiroyuki Kusuhara, Emi Kimoto

Renal transporters play a critical role in the renal secretion of prescription drugs and endogenous metabolites. Inhibition of these transporters can increase the plasma exposure of a co-administered drug by reducing its renal clearance, potentially resulting in clinically significant drug-drug interactions (DDIs). The ICH M12 guideline promotes the use of endogenous substrates as biomarkers offers a promising approach for assessing transporter inhibition during early-phase clinical studies, potentially reducing reliance on traditional probe-based DDI trials. This strategy may reduce or eliminate the need for dedicated DDI studies using exogenous probe substrates, thereby streamlining drug development and advancing precision medicine. This review provides an overview of the discovery, evaluation, and application of renal transporter biomarkers-specifically endogenous metabolites-in the context of transporter-mediated DDI risk assessment. We highlight the use of in vitro and in vivo models, including transporter-overexpressing cell systems, knockout mice, and clinical DDI samples, to identify and validate biomarkers for renal transporters. Human genetic studies further support biomarker discovery by linking transporter variants to metabolite levels. Analytical tools like targeted and untargeted metabolomic approaches are essential for biomarker identification and quantification. Additionally, physiologically based pharmacokinetic (PBPK) modeling is discussed as a critical tool for translating biomarker data into clinical DDI predictions.

肾转运蛋白在处方药物和内源性代谢物的肾脏分泌中起关键作用。抑制这些转运蛋白可通过降低药物的肾脏清除率而增加药物在血浆中的暴露，从而可能导致临床显著的药物-药物相互作用（ddi）。ICH M12指南提倡使用内源性底物作为生物标志物，为早期临床研究中评估转运蛋白抑制提供了一种有希望的方法，可能减少对传统基于探针的DDI试验的依赖。这种策略可以减少或消除使用外源性探针底物进行专门的DDI研究的需要，从而简化药物开发和推进精准医学。本文综述了肾转运蛋白生物标志物（特别是内源性代谢物）在转运蛋白介导的DDI风险评估中的发现、评估和应用。我们强调使用体外和体内模型，包括转运蛋白过表达的细胞系统、敲除小鼠和临床DDI样本，来识别和验证肾脏转运蛋白的生物标志物。人类遗传学研究通过将转运体变异与代谢物水平联系起来，进一步支持生物标志物的发现。像靶向和非靶向代谢组学方法这样的分析工具对于生物标志物的鉴定和定量是必不可少的。此外，基于生理的药代动力学（PBPK）建模是将生物标志物数据转化为临床DDI预测的关键工具。

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引用次数: 0

Positive implications of PBPK platform qualification for predicting drug–drug interactions: Taking on cracks only to see bigger gaps! PBPK平台资格对预测药物-药物相互作用的积极影响：采取裂缝只会看到更大的差距！

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-24 DOI: 10.1016/j.dmpk.2025.101514

Amin Rostami-Hodjegan

In this mini-review, the readers are provided with series of key references which highlight the latest trends in the space of physiologically-based pharmacokinetics (PBPK) concerning assessment and management of drug-drug interactions (DDI). Over the last two decades such applications have moved from an academic nicety to industrial necessity, and then regulatory requirement. However, the regulatory uptake has not been uniform and it has not taken the same path. These have been a reflection of the set up in various regulatory agencies and their breadth and depth of work-force, centralized or de-centralized nature of geographical distribution of assessors, existence or lack of internal research groups to examine multi-layer large scale models and many other factors. However, despite these operational differences, recent qualification opinion by EMA on platforms used for PBPK evaluation in the space of DDI is a significant step that heralds a general worldwide consensus for harmonization in use of these new technologies as a follow up to efforts within International Harmonization Committee in the space via publication of their M12 Guidance. Readers will get to know the journey that has taken us to this point and some forthcoming directions on expansion of applications.

在这篇小型综述中，读者将获得一系列重要参考文献，这些文献强调了基于生理的药代动力学（PBPK）领域有关药物-药物相互作用（DDI）评估和管理的最新趋势。在过去的二十年里，这种应用已经从学术上的精确变成了工业上的需要，然后是监管上的要求。然而，监管力度并不统一，采取的道路也不尽相同。这反映了各种管理机构的设置及其工作人员的广度和深度、评估人员地理分布的集中或分散性质、是否存在内部研究小组以审查多层大型模型和许多其他因素。然而，尽管存在这些操作上的差异，EMA最近对DDI领域用于PBPK评估的平台提出的资格意见是一个重要的步骤，预示着全球对这些新技术的使用达成普遍共识，作为国际协调委员会通过发布M12指南在该领域所做努力的后续行动。读者将会了解到我们是如何走到这一步的，以及未来扩展应用程序的一些方向。

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引用次数: 0

Evaluation of OATP1B inhibitory potential using an endogenous biomarker coproporphyrin-I in new drug applications: Case reports submitted by 2024 内源性生物标志物coproporphyrin-I在新药应用中的抑制潜力评估：2024年提交的病例报告。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-17 DOI: 10.1016/j.dmpk.2025.101513

Ryosuke Watari

Coproporphyrin-I (CP-I), an endogenous biomarker for organic anion transporting polypeptide (OATP) 1B, is a critical tool for evaluating the inhibitory potential of OATP1B in humans. The final International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12 guideline (Step 4) recognizes CP-I as a validated biomarker for this purpose. In addition, the area under the concentration–time curve (AUC) ratio and the maximum concentration (C_max) ratio of CP-I have been used as indices to assess OATP1B inhibition, with the cutoff value set at 1.25. Because ICH M12 now describes the application of CP-I as a biomarker for evaluating the inhibitory potential of OATP1B, CP-I data are expected to be increasingly used in future new drug applications (NDAs). This review presents case studies of NDAs submitted by 2024 that incorporated CP-I to evaluate the OATP1B inhibitory potential of new molecular entities before the finalization of ICH M12 Step 4. In addition, considerations and perspectives regarding the evaluation of OATP1B inhibition using CP-I are discussed. These examples can serve as references for future applications using CP-I and the regulatory acceptance of other endogenous biomarkers, such as N¹-methylnicotinamide and pyridoxic acid, as described in the ICH M12 guideline.

Coproporphyrin-I （CP-I）是有机阴离子转运多肽（OATP） 1B的内源性生物标志物，是评估人体OATP1B抑制潜力的重要工具。最终的国际人用药品技术要求协调委员会（ICH） M12指南（步骤4）承认cp - 1是用于此目的的经过验证的生物标志物。另外，以浓度-时间曲线下面积（AUC）比和cp - 1的最大浓度（Cmax）比作为评价OATP1B抑制作用的指标，临界值设为1.25。由于ICH M12现在描述了cp - 1作为评估OATP1B抑制潜力的生物标志物的应用，cp - 1数据有望在未来的新药应用（NDAs）中得到越来越多的应用。本综述介绍了2024年提交的纳入cp - 1的nda的案例研究，以评估ICH M12步骤4最终确定之前新分子实体的OATP1B抑制潜力。此外，本文还讨论了利用cp - 1评价OATP1B抑制作用的考虑和展望。这些例子可以作为今后使用cp - 1和其他内源性生物标志物（如ICH M12指南中描述的n1 -甲基烟酰胺和吡哆酸）的监管认可的参考。

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引用次数: 0

Future directions in drug-drug interaction evaluations: Industry perspective on the ICH M12 guidance 药物相互作用评价的未来方向：ICH M12指南的行业观点。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-12 DOI: 10.1016/j.dmpk.2025.101512

Kenichi Umehara , Andrew Harrell , Chandra Prakash , Constanze Hilgendorf , T. Eric Ballard , Felix Huth , Justine Badée , Licong Jiang , Manoli Vourvahis , Natasa Pajkovic , Neil Parrott , Nilay Thakkar , Patrik Marroum , Ronald Laethem , Shiyao Xu , Yuan Chen

The ICH M12 Guidance, adopted by the International Council for Harmonisation in 2024, provides a global framework for assessing drug-drug interaction (DDI) risks mediated by metabolic enzymes and drug transporters. The DDI Discussion Group in the International Consortium for Innovation and Quality identifies key challenges in the guidance. In vitro challenges include accounting for protein binding, mitigating overestimations of DDI risks, and interpreting weak enzyme inhibition or induction effects. A case study explores cytochrome P450 (CYP) induction risks by major metabolites. The complexities of UDP-glucuronosyltransferase (UGT) and transporter inhibition or induction are contextualized. Clearance pathway evaluations for low turnover compounds and UGT or transporter substrates are also summarized for object DDIs. Clinically, challenges include the need for validated endogenous biomarkers to improve DDI risk assessments and finding alternatives to rifampin for CYP induction and Organic Anion Transporting polypeptide 1B (OATP1B) inhibition due to nitrosamine: reduced and non-selective induction by drugs like carbamazepine and phenytoin or non-selective OATP inhibition by cyclosporine. Further complexities involve therapeutic-protein DDIs, transporter-enzyme interplay and compounds acting as simultaneous inducers and time-dependent inhibitors. Addressing these gaps requires collaborative efforts to refine predictive models to improve in vitro-in vivo correlations, and to enhance drug development and patient safety.

国际协调理事会于2024年通过的ICH M12指南为评估代谢酶和药物转运体介导的药物-药物相互作用（DDI）风险提供了一个全球框架。国际创新与质量联盟的DDI讨论小组确定了指南中的主要挑战。体外研究面临的挑战包括蛋白质结合、减轻对DDI风险的高估，以及解释弱酶抑制或诱导效应。一个案例研究探讨了主要代谢物诱导细胞色素P450 （CYP）的风险。复杂的udp -葡萄糖醛酸糖基转移酶（UGT）和转运体的抑制或诱导是背景。对低周转率化合物和UGT或转运体底物的清除途径评价也进行了总结。临床上面临的挑战包括需要经过验证的内源性生物标志物来改善DDI风险评估，以及寻找利福平的替代品来诱导亚硝胺引起的CYP和有机阴离子转运多肽1B （OATP1B）抑制：卡马西平和苯妥英等药物减少和非选择性诱导，或环sporine非选择性抑制OATP。进一步的复杂性涉及治疗蛋白ddi，转运酶相互作用以及同时作为诱导剂和时间依赖性抑制剂的化合物。解决这些差距需要合作努力来完善预测模型，以改善体内外相关性，并加强药物开发和患者安全。

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引用次数: 0

Current status of prediction of IL-6 mediated cytochrome P450 activity modulation using in vitro data and PBPK modeling 利用体外数据和PBPK模型预测IL-6介导的细胞色素P450活性调节的现状

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-09 DOI: 10.1016/j.dmpk.2025.101510

Viktor Georgiev , Isabelle Anderka , Delia Bucher , Lena Preiss , Jitao David Zhang , Kenichi Umehara , Neil Parrott

This review focuses on use of in vitro data and physiologically based pharmacokinetic (PBPK) modeling to predict disease-drug and therapeutic-protein-drug interactions for Cytochrome P450 CYP substrates mediated by interleukin-6 (IL-6). We review current understanding of the mechanisms of inflammatory IL-6 release (both with and without drug treatment), and provide an overview of the in vitro models for assessing CYP suppression by IL-6. Furthermore, past applications and current status of PBPK modeling in this context were comprehensively reviewed. We then highlight a recently published, more mechanistic PBPK model that treats IL-6 as a therapeutic protein and links CYP suppression to the IL-6-receptor complex concentration in the liver and gut interstitial spaces. This new model demonstrates good predictive performance across various patient populations and is able to simulate clinical outcomes based on a mechanistic pharmacokinetic model integrating known IL-6 receptor biology. Therefore we anticipate increased impact on regulatory decisions. However, gaps remain in understanding IL-6 kinetics and the translation of in vitro data to in vivo predictions and we suggest that further progress will be made by applying mechanistic modeling to guide future experimental work and generate a better understanding of IL-6's influence on co-administered small molecule drugs.

本文综述了利用体外数据和基于生理的药代动力学（PBPK）模型来预测白细胞介素-6 （IL-6）介导的细胞色素P450 CYP底物的疾病-药物和治疗-蛋白质-药物相互作用。我们回顾了目前对炎症IL-6释放机制的理解（包括有和没有药物治疗），并概述了评估IL-6抑制CYP的体外模型。并对PBPK模型在这方面的应用现状进行了综述。然后，我们重点介绍了最近发表的一种更机械的PBPK模型，该模型将IL-6作为治疗蛋白，并将CYP抑制与肝脏和肠间质间隙中的IL-6受体复合物浓度联系起来。这个新模型在不同的患者群体中表现出良好的预测性能，并且能够基于整合已知IL-6受体生物学的机制药代动力学模型模拟临床结果。因此，我们预计监管决策将受到更大的影响。然而，在了解IL-6动力学和将体外数据转化为体内预测方面仍然存在差距，我们建议通过应用机制建模来指导未来的实验工作，并更好地了解IL-6对共给小分子药物的影响，从而取得进一步的进展。

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引用次数: 0

Role of metabolites in drug-drug interactions 代谢物在药物-药物相互作用中的作用。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-08 DOI: 10.1016/j.dmpk.2025.101511

Nina Isoherranen

Since the publication of the metabolites in safety testing (MIST) guidance by the US FDA in 2009, there has been continuous interest and expansion in research aimed at predicting and characterizing circulating metabolites. Several systematic reviews and original research articles have been published to assess the role of metabolites in drug-drug interactions. Abundant circulating metabolites have been found to be common with classic cytochrome P450 (CYP) enzyme inhibitors and with new drugs in development. This has raised the need for better tools to predict significant circulating metabolites from preclinical data to streamline metabolite testing. This review summarizes the current recommendations for metabolite testing, evaluates the existing data on reversible and time-dependent inhibition of CYP enzymes by circulating metabolites, and explores the potential inhibition of drug transporters by circulating metabolites. The possible role of metabolites in induction of CYP enzymes is also discussed. The mathematical methods to incorporate multiple precipitants into risk assessment and quantitative prediction methods for inhibition and induction are summarized. Finally, the unique considerations regarding PBPK modeling of metabolites are discussed to highlight potential differences in the metabolite liver concentrations used in static versus more dynamic PBPK prediction methods.

自2009年美国FDA发布代谢物安全测试（MIST）指南以来，人们对循环代谢物预测和表征的研究不断感兴趣并扩大。已经发表了一些系统综述和原创研究文章来评估代谢物在药物-药物相互作用中的作用。经典的细胞色素P450 （CYP）酶抑制剂和正在开发的新药都有丰富的循环代谢物。这就需要更好的工具来预测临床前数据中重要的循环代谢物，以简化代谢物测试。本文综述了目前代谢物检测的建议，评估了循环代谢物对CYP酶的可逆和时间依赖性抑制的现有数据，并探讨了循环代谢物对药物转运体的潜在抑制作用。还讨论了代谢物在诱导CYP酶的可能作用。综述了将多种沉淀剂纳入风险评估的数学方法以及抑制和诱导的定量预测方法。最后，讨论了代谢物PBPK建模的独特考虑因素，以突出在静态和更动态的PBPK预测方法中使用的代谢物肝脏浓度的潜在差异。

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引用次数: 0

A novel quantitative assessment of formed reactive metabolites by double trapping with [3H]glutathione and [14C]cyanide [3H]谷胱甘肽和[14C]氰化物双捕获形成的反应性代谢物的一种新的定量评估。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-12-01 DOI: 10.1016/j.dmpk.2025.101504

Tomoyuki Kawachi , Tatsuki Fukami , Miki Nakajima

Drug-induced liver injury often arises from reactive metabolites (RMs) produced in the liver, making it crucial to assess RM formation rates from drug candidates. Conventional assays using glutathione (GSH) effectively trap soft electrophilic RMs but fail to detect hard electrophiles. To address this, we developed a double trapping assay employing [³H]GSH and [¹⁴C]cyanide as soft and hard nucleophilic reagents, respectively. This assay was applied to 25 drugs chosen based on safety profiles. Eight drugs were exclusively trapped by [³H]GSH, while 11 were trapped by [¹⁴C]cyanide or both reagents, demonstrating that a double trapping assay provides a more comprehensive detection method for both soft and hard RMs. Multiplying RM formation rates by daily doses allowed almost complete differentiation between withdrawn/black boxed warning drugs and safer ones. Radio-LCMS analysis provided detailed insights into the substructures of drug candidates responsible for RM production. Interestingly, it was discovered that GSH-based assays sometimes fail to detect certain RMs due to the presence of dithiothreitol in commercial [³H]GSH. This study highlights the efficacy of the double trapping assay using [³H]GSH and [¹⁴C]cyanide in accurately and comprehensively detecting RMs. Furthermore, it offers valuable structural information to minimize RM formation during early drug discovery.

药物性肝损伤通常由肝脏产生的反应性代谢物（RM）引起，因此评估候选药物的RM形成率至关重要。使用谷胱甘肽（GSH）的常规检测方法可以有效捕获软亲电均方根，但无法检测硬亲电均方根。为了解决这个问题，我们开发了一种双捕获实验，分别使用[3H]GSH和[14C]氰化物作为软亲核试剂和硬亲核试剂。该方法应用于25种基于安全性特征选择的药物。8种药物完全被[3H]GSH捕获，11种药物被[14C]氰化物捕获或同时被两种试剂捕获，表明双捕获法为软硬均方根提供了更全面的检测方法。将RM形成率乘以每日剂量，几乎可以完全区分停药/黑框警告药物和更安全的药物。无线电- lcms分析提供了对负责原料药生产的候选药物亚结构的详细见解。有趣的是，研究发现，基于谷胱甘肽的检测有时无法检测到某些有效值，因为在商业[3H]谷胱甘肽中存在二硫苏糖醇。本研究强调了[3H]GSH和[14C]氰化物双捕集法准确、全面地检测均方根值的有效性。此外，它提供了有价值的结构信息，以减少早期药物发现过程中RM的形成。

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引用次数: 0

The rational use of PBPK to assess the changing DDI liability in pediatrics: Model qualification and the move towards best practice 合理使用PBPK评估儿科不断变化的DDI责任：模型资格和走向最佳实践。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-11-26 DOI: 10.1016/j.dmpk.2025.101509

Trevor N. Johnson , Jean Dinh , Roz Southall , Amin Rostami-Hodjegan

Many drug-drug interactions (DDIs) in the pediatric population are managed based on data generated in adults, however this is done with little clinical evidence and the assumption of DDIs being similar between adults and pediatric may not be correct. Physiologically Based Pharmacokinetic models have been used extensively to predict DDIs in adults and this evidence is now being accepted by regulators worldwide and in certain cases information from PBPK is feeding directly into the drug labels. Because pediatric PBPK models account for age related changes in physiology and biochemistry they are ideally placed to extrapolate DDI liability from adults to children. However, marrying together all relevant system factors such as ontogeny of enzymes and hepatic blood flow with drug related factors e.g. extraction ratio and fraction unbound is important and is an active area of research. This review will highlight the need for dynamic rather than static PBPK pediatric DDI predictions with a view to recommending the best practice approach.

儿童人群中的许多药物-药物相互作用（ddi）是基于成人数据进行管理的，然而这是在很少的临床证据的基础上完成的，并且成人和儿童之间ddi相似的假设可能是不正确的。基于生理的药代动力学模型已被广泛用于预测成人的ddi，这一证据现在已被世界各地的监管机构所接受，在某些情况下，PBPK的信息直接输入到药物标签中。由于儿童PBPK模型考虑了与年龄相关的生理和生物化学变化，因此它们是推断成人对儿童DDI责任的理想选择。然而，将所有相关的系统因素（如酶的个体发生和肝血流）与药物相关因素（如提取率和未结合分数）结合起来是重要的，也是一个活跃的研究领域。本综述将强调动态而非静态PBPK儿科DDI预测的必要性，以推荐最佳实践方法。

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引用次数: 0

Cytochrome P450 reaction phenotyping: State of the art 细胞色素P450反应表型：最新进展。

IF 2.2 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2025-11-10 DOI: 10.1016/j.dmpk.2025.101508

Elaine Tseng, R. Scott Obach

Cytochrome P450 reaction phenotyping refers to the in vitro experimental approach that estimates the quantitative contributions of individual P450 enzymes to the metabolism of a drug. Methods for this are well-established and have existed for over three decades and include the use of selective inhibitors, individually expressed P450 enzymes, and human-derived in vitro systems such as liver microsomes and hepatocytes. The results from P450 reaction phenotyping experiments are used to inform patient safety, clinical trial designs, and physiologically-based pharmacokinetic models, and this information is an expectation from government regulatory authorities when developing a new drug candidate. Despite widespread use, P450 reaction phenotyping methods possess shortcomings. These include sub-optimal selectivity of P450 inhibitors, scaling factors that can differ among substrates, challenges measuring low turnover substrates, and considerations of non-P450 routes of drug clearance (e.g. active transport, other drug metabolizing enzyme families). A recently described “sequential qualitative-then-quantitative” approach to P450 reaction phenotyping is described along with a more comprehensive experimental design that considers incomplete selectivity of P450 inhibitors. This approach addresses some of the aforementioned shortcomings, however it is still important to consider the contribution of P450 enzymes to the overall dispositional profile that is obtained from in vivo studies, such as radiolabel human absorption/distribution/metabolism/excretion (ADME) studies.

细胞色素P450反应表型是指体外实验方法，估计单个P450酶对药物代谢的定量贡献。这方面的方法已经建立并存在了30多年，包括使用选择性抑制剂、单独表达的P450酶和人类来源的体外系统，如肝微粒体和肝细胞。P450反应表型实验的结果用于为患者安全性、临床试验设计和基于生理的药代动力学模型提供信息，这些信息是政府监管机构在开发新的候选药物时的期望。尽管广泛使用，P450反应表型方法有缺点。其中包括P450抑制剂的次优选择性，底物之间的比例因子可能不同，测量低周转底物的挑战，以及非P450药物清除途径的考虑（例如主动运输，其他药物代谢酶家族）。最近描述了一种“连续定性-然后定量”的P450反应表型方法，以及一种考虑P450抑制剂不完全选择性的更全面的实验设计。这种方法解决了前面提到的一些缺点，但是考虑P450酶对体内研究（如放射性标记人体吸收/分布/代谢/排泄（ADME）研究）获得的整体配置概况的贡献仍然很重要。

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引用次数: 0