人类和非临床物种肝脏转运体及药物代谢酶的个体发生
Ontogeny of Hepatic Transporters and Drug-Metabolizing Enzymes in Humans and in Nonclinical Species.
作者信息
van Groen B D, Nicolaï J, Kuik A C, Van Cruchten S, van Peer E, Smits A, Schmidt S, de Wildt S N, Allegaert K, De Schaepdrijver L, Annaert P, Badée J
机构信息
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.D.v.G., K.A.); Development Science, UCB BioPharma SRL, Braine-l'Alleud, Belgium (J.N.); Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (A.C.K.); Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium (S.V.C.); Fendigo sa/nvbv, An Alivira Group Company, Brussels, Belgium (E.v.P.); Department of Development and Regeneration KU Leuven, Leuven, Belgium (A.S.); Neonatal intensive care unit, University Hospitals Leuven, Leuven, Belgium (A.S.); Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida (S.S.); Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands (S.N.d.W.); Departments of Development and Regeneration and of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (K.A.); Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands (K.A.); Nonclinical Safety, Janssen R&D, Beerse, Belgium (L.D.S.); Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (P.A.); and Department of PK Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.B.).
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands (B.D.v.G., K.A.); Development Science, UCB BioPharma SRL, Braine-l'Alleud, Belgium (J.N.); Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands (A.C.K.); Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium (S.V.C.); Fendigo sa/nvbv, An Alivira Group Company, Brussels, Belgium (E.v.P.); Department of Development and Regeneration KU Leuven, Leuven, Belgium (A.S.); Neonatal intensive care unit, University Hospitals Leuven, Leuven, Belgium (A.S.); Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida (S.S.); Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands (S.N.d.W.); Departments of Development and Regeneration and of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (K.A.); Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands (K.A.); Nonclinical Safety, Janssen R&D, Beerse, Belgium (L.D.S.); Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium (P.A.); and Department of PK Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland (J.B.)
出版信息
Pharmacol Rev. 2021 Apr;73(2):597-678. doi: 10.1124/pharmrev.120.000071.
The liver represents a major eliminating and detoxifying organ, determining exposure to endogenous compounds, drugs, and other xenobiotics. Drug transporters (DTs) and drug-metabolizing enzymes (DMEs) are key determinants of disposition, efficacy, and toxicity of drugs. Changes in their mRNA and protein expression levels and associated functional activity between the perinatal period until adulthood impact drug disposition. However, high-resolution ontogeny profiles for hepatic DTs and DMEs in nonclinical species and humans are lacking. Meanwhile, increasing use of physiologically based pharmacokinetic (PBPK) models necessitates availability of underlying ontogeny profiles to reliably predict drug exposure in children. In addition, understanding of species similarities and differences in DT/DME ontogeny is crucial for selecting the most appropriate animal species when studying the impact of development on pharmacokinetics. Cross-species ontogeny mapping is also required for adequate translation of drug disposition data in developing nonclinical species to humans. This review presents a quantitative cross-species compilation of the ontogeny of DTs and DMEs relevant to hepatic drug disposition. A comprehensive literature search was conducted on PubMed Central: Tables and graphs (often after digitization) in original manuscripts were used to extract ontogeny data. Data from independent studies were standardized and normalized before being compiled in graphs and tables for further interpretation. New insights gained from these high-resolution ontogeny profiles will be indispensable to understand cross-species differences in maturation of hepatic DTs and DMEs. Integration of these ontogeny data into PBPK models will support improved predictions of pediatric hepatic drug disposition processes. SIGNIFICANCE STATEMENT: Hepatic drug transporters (DTs) and drug-metabolizing enzymes (DMEs) play pivotal roles in hepatic drug disposition. Developmental changes in expression levels and activities of these proteins drive age-dependent pharmacokinetics. This review compiles the currently available ontogeny profiles of DTs and DMEs expressed in livers of humans and nonclinical species, enabling robust interpretation of age-related changes in drug disposition and ultimately optimization of pediatric drug therapy.
肝脏是主要的排泄和解毒器官，决定了内源性化合物、药物及其他外源性物质的暴露情况。药物转运体（DTs）和药物代谢酶（DMEs）是药物处置、疗效及毒性的关键决定因素。从围生期到成年期，它们的mRNA和蛋白质表达水平以及相关功能活性的变化会影响药物处置。然而，非临床物种和人类肝脏中DTs和DMEs的高分辨率个体发育图谱尚不存在。同时，基于生理的药代动力学（PBPK）模型的使用日益增加，这就需要有潜在的个体发育图谱来可靠地预测儿童的药物暴露情况。此外，了解DT/DME个体发育中的物种异同对于研究发育对药代动力学的影响时选择最合适的动物物种至关重要。在将非临床物种发育过程中的药物处置数据充分转化为人类数据时，也需要进行跨物种个体发育图谱绘制。本综述呈现了与肝脏药物处置相关的DTs和DMEs个体发育的定量跨物种汇编。我们在PubMed Central上进行了全面的文献检索：利用原始手稿中的表格和图表（通常在数字化之后）提取个体发育数据。来自独立研究的数据在被汇编成图表以作进一步解读之前，先进行了标准化和归一化处理。从这些高分辨率个体发育图谱中获得的新见解对于理解肝脏DTs和DMEs成熟过程中的跨物种差异将不可或缺。将这些个体发育数据整合到PBPK模型中将有助于改进对儿童肝脏药物处置过程的预测。意义声明：肝脏药物转运体（DTs）和药物代谢酶（DMEs）在肝脏药物处置中起关键作用。这些蛋白质表达水平和活性的发育变化驱动了年龄依赖性药代动力学。本综述汇编了人类和非临床物种肝脏中表达的DTs和DMEs目前可用的个体发育图谱，从而能够对药物处置中与年龄相关的变化进行有力解读，并最终优化儿科药物治疗。
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