Pfizer Worldwide Research & Development, Clinical Pharmacology, Cambridge, Massachusetts (A.S.-B.) and Pfizer Worldwide Research & Development, Pharmacokinetics, Dynamics, and Metabolism, Groton, Connecticut (R.S.O.)
Pfizer Worldwide Research & Development, Clinical Pharmacology, Cambridge, Massachusetts (A.S.-B.) and Pfizer Worldwide Research & Development, Pharmacokinetics, Dynamics, and Metabolism, Groton, Connecticut (R.S.O.).
Drug Metab Dispos. 2018 Nov;46(11):1556-1561. doi: 10.1124/dmd.118.084293.
This commentary summarizes expert mini-reviews and original research articles that have been assembled in a special issue on novel models of drug metabolism and disposition. The special issue consists of research articles or reviews on novel static or micro-flow based models of the intestine, liver, eye, and kidney. This issue reviews static intestinal systems like mucosal scrapings and cryopreserved intestinal enterocytes, as well as novel bioengineered or chemically engineered intestinal models derived from primary human tissue, iPSCs, enteroids, and crypts. Experts have reviewed hepatic systems like cryopermeabilized Metmax hepatocytes and longer term, hepatocyte coculture system from HREL, yielding in vivo-like primary and secondary drug metabolite profiles. Additional liver models, including micropattern hepatocyte coculture, 3D liver spheroids, and microflow systems, applicable to the study of drug disposition and toxicology have also been reviewed. In this commentary, we have outlined expert opinions and current efforts on hepatic- and nephrotoxicity models. Ocular disposition models including corneal permeability models have been included within this special issue. This commentary provides a summary of in vivo mini-reviews of the issue, which have discussed the applications and drawbacks of pig and humanized mice models of P450, UGT, and rat organic anionic transporting polypeptide 1a4. While not extensively reviewed, novel positron emissions tomography imaging-based approaches to study the distribution of xenobiotics have been highlighted. This commentary also outlines in vitro and in vivo models of drug metabolism derived from breakthrough genetic, chromosomal, and tissue engineering techniques. The commentary concludes by providing a futuristic view of the novel models discussed in this issue.
本评论总结了专门讨论新型药物代谢和处置模型的特刊中汇集的专家小型评论和原始研究文章。该特刊包含关于肠道、肝脏、眼睛和肾脏的新型静态或微流模型的研究文章或评论。本专题评论了静态肠道系统，如黏膜刮取物和冷冻保存的肠上皮细胞，以及源自原代人组织、iPSC、类器官和隐窝的新型生物工程或化学工程化的肠模型。专家们还评论了诸如冷冻通透的 Metmax 肝细胞和来自 HREL 的更长期的肝细胞共培养系统等肝系统，这些系统产生了类似于体内的原发性和次级药物代谢物谱。还评论了其他肝模型，包括微图案肝细胞共培养、3D 肝球体和微流系统，这些模型适用于药物处置和毒理学的研究。在本评论中，我们概述了关于肝毒性和肾毒性模型的专家意见和当前努力。本特刊还包括眼处置模型，包括角膜透过性模型。本评论提供了对该问题的体内小型评论的总结，其中讨论了猪和人源化小鼠模型在 P450、UGT 和大鼠有机阴离子转运多肽 1a4 中的应用和缺点。虽然没有广泛评论，但强调了基于正电子发射断层扫描成像的研究外源性物质分布的新方法。本评论还概述了源自突破性遗传、染色体和组织工程技术的药物代谢体外和体内模型。最后，本评论对本特刊中讨论的新型模型进行了前瞻性展望。
