新型体外肝脏代谢模型及其应用进展

doi:10.12092/j.issn.1009-2501.2026.07.014

中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (7): 975-989.doi: 10.12092/j.issn.1009-2501.2026.07.014

新型体外肝脏代谢模型及其应用进展

卢思翰¹^,²(), 鲍广霖¹^,², 孙建国¹^,²^,³^,*()

1. 中国药科大学江苏省药物代谢动力学研究重点实验室，南京 210009，江苏
2. 中国药科大学多靶标天然药物全国重点实验室，南京 210009，江苏
3. 中国医学科学院，“中药复杂组分PK-PD结合研究”创新单元，北京 100730

收稿日期:2025-12-11 修回日期:2026-02-13 出版日期:2026-07-26 发布日期:2026-08-04
通讯作者: 孙建国 E-mail:3223071772@stu.cpu.edu.cn;jgsun@cpu.edu.cn
作者简介:卢思翰，男，硕士研究生，研究方向：临床前药代动力学。E-mail：3223071772@stu.cpu.edu.cn
基金资助:
中国医学科学院医学与健康科技创新工程项目（2021-I2M-5-011）

Novel in vitro liver metabolism models and their applications progress

Sihan LU¹^,²(), Guanglin BAO¹^,², Jianguo SUN¹^,²^,³^,*()

1. Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
2. State key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
3. Innovative Unit "PK-PD Combination Research on Complex Components of Traditional Chinese Medicines", Chinese Academy of Medical Sciences, Beijing 100730, China

Received:2025-12-11 Revised:2026-02-13 Online:2026-07-26 Published:2026-08-04
Contact: Jianguo SUN E-mail:3223071772@stu.cpu.edu.cn;jgsun@cpu.edu.cn

摘要/Abstract

摘要：

药物的肝脏代谢研究对药物开发、临床用药指导及药物安全性评估具有重要意义。传统体外肝脏模型虽应用广泛，但在功能维持、预测准确性与生理模拟方面存在局限性，促使多种新型体外肝脏模型被开发。现有综述多侧重于新型模型构建技术的介绍或性能的比较，而系统梳理不同新型模型在药物代谢研究中应用特点的文献较少。在综述近年来新型体外肝脏模型特点及其所采用新技术的基础上，本文进一步将模型功能特性与具体药物代谢研究应用场景对应分析，归纳其在代谢稳定性、代谢物鉴定与药物相互作用评估等方面的表现。以期为体外模型的合理选择与规范化应用提供参考，支持药物的临床前研究与临床应用。

关键词: 肝脏, 生物转化, 体外研究, 代谢清除率, 药物相互作用

Abstract:

Studies of hepatic drug metabolism are crucial for drug development, clinical dosing guidance, and assessment of drug safety. Although traditional in vitro liver models have been widely used, their limitations in maintaining hepatic function, predictive accuracy, and physiological fidelity have spurred the development of various advanced in vitro liver models. Previous reviews have focused on the technologies used for constructing novel models or on comparative evaluations of their performance, whereas systematic analyses of the application characteristics of different advanced models in drug metabolism research remain limited. Based on a comprehensive review of recent advanced in vitro liver models and the novel technologies they employ, this article further aligns model functional characteristics with specific drug-metabolism research scenarios and summarizes their performance in metabolic stability assessment, metabolite identification, and the evaluation of drug–drug interactions. This review aims to provide guidance for the rational selection and standardized application of in vitro models, thereby supporting preclinical research and clinical use of drugs.

Key words: liver, biotransformation, in vitro techniques, metabolic clearance rate, drug interaction

中图分类号:

R969.1

卢思翰, 鲍广霖, 孙建国. 新型体外肝脏代谢模型及其应用进展[J]. 中国临床药理学与治疗学, 2026, 31(7): 975-989.

Sihan LU, Guanglin BAO, Jianguo SUN. Novel in vitro liver metabolism models and their applications progress[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(7): 975-989.

图/表 3

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Model	Common cell sources	Cell culture techniques	Advantages	Limitations
Sandwich culture model	PHH	Sandwich culture	Well-defined bile canaliculi, sustained metabolic function for extended periods, suitable for hepatobiliary drug-excretion and transporter studies	Limited physiological relevance in two-dimensional formats, limited maintenance of metabolic function
Spheroid model	PHH, iPSC, HepG2, HepaRG	ULA plate culture, hanging drop culture, hydrogel encapsulation, micropatterned plate culture, cell co-culture	High-throughput; long-term maintenance of metabolic function, physiological polarity and extracellular matrix, suitable for metabolism studies of low-clearance drugs	Prone to necrotic-core formation, heterogeneous spheroid formation, challenging real-time monitoring of spheroid interiors
Liver organoid model	Liver tissue, iPSC	Cell co-culture, hydrogel encapsulation, scaffold engineering	High fidelity to organ biology, long-term maintenance of metabolic function, suitable for studies of inter-individual variability	Prone to necrotic-core formation, complex culture procedures, high cost
Liver-on-a-chip	PHH, iPSC, HepG2, HepaRG	Microfluidic integration, micropatterned culture, cell co-culture, three-dimensional scaffold culture	High physiological relevance, Reduced susceptibility to central necrosis, long-term maintenance of metabolic function, real-time online monitoring, precise control of microenvironmental physiological parameters, suitable for complex metabolic studies	High technical barrier, high cost

Model	Common cell sources	Cell culture techniques	Advantages	Limitations
Sandwich culture model	PHH	Sandwich culture	Well-defined bile canaliculi, sustained metabolic function for extended periods, suitable for hepatobiliary drug-excretion and transporter studies	Limited physiological relevance in two-dimensional formats, limited maintenance of metabolic function
Spheroid model	PHH, iPSC, HepG2, HepaRG	ULA plate culture, hanging drop culture, hydrogel encapsulation, micropatterned plate culture, cell co-culture	High-throughput; long-term maintenance of metabolic function, physiological polarity and extracellular matrix, suitable for metabolism studies of low-clearance drugs	Prone to necrotic-core formation, heterogeneous spheroid formation, challenging real-time monitoring of spheroid interiors
Liver organoid model	Liver tissue, iPSC	Cell co-culture, hydrogel encapsulation, scaffold engineering	High fidelity to organ biology, long-term maintenance of metabolic function, suitable for studies of inter-individual variability	Prone to necrotic-core formation, complex culture procedures, high cost
Liver-on-a-chip	PHH, iPSC, HepG2, HepaRG	Microfluidic integration, micropatterned culture, cell co-culture, three-dimensional scaffold culture	High physiological relevance, Reduced susceptibility to central necrosis, long-term maintenance of metabolic function, real-time online monitoring, precise control of microenvironmental physiological parameters, suitable for complex metabolic studies	High technical barrier, high cost

Compound	Fold error
Compound	HepaRG	SCC	Suspension	MPCC	Sph
Diazepam	0.2	0.6	NA	1.1	0.8
Etodolac	0.8	0.7	0.3	0.5	1.6
Glipizide	0.2	0.3	0.8	0.4	0.5
Ketoprofen	0.9	1.6	0.7	2.2	0.9
Ondansetron	1.4	1.0	1.8	2.5	1.8
Theophylline	NA	ND	NA	1.7	3.5
Tolbutamide	ND	1.9	4.9	1.2	2.3
Warfarin	1.3	1.0	NA	2.3	1.4

Compound	Fold error
Compound	HepaRG	SCC	Suspension	MPCC	Sph
Diazepam	0.2	0.6	NA	1.1	0.8
Etodolac	0.8	0.7	0.3	0.5	1.6
Glipizide	0.2	0.3	0.8	0.4	0.5
Ketoprofen	0.9	1.6	0.7	2.2	0.9
Ondansetron	1.4	1.0	1.8	2.5	1.8
Theophylline	NA	ND	NA	1.7	3.5
Tolbutamide	ND	1.9	4.9	1.2	2.3
Warfarin	1.3	1.0	NA	2.3	1.4

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新型体外肝脏代谢模型及其应用进展

Novel in vitro liver metabolism models and their applications progress

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