Comparison of Rat and Human Pulmonary Metabolism Using Precision-cut Lung Slices (PCLS).

Drug metabolism letters Pub Date : 2019-01-01 DOI:10.2174/1872312812666181022114622

Yildiz Yilmaz, Gareth Williams, Markus Walles, Nenad Manevski, Stephan Krähenbühl, Gian Camenisch

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引用次数: 16

Abstract

Background: Although the liver is the primary organ of drug metabolism, the lungs also contain drug-metabolizing enzymes and may, therefore, contribute to the elimination of drugs. In this investigation, the Precision-cut Lung Slice (PCLS) technique was standardized with the aims of characterizing and comparing rat and human pulmonary drug metabolizing activity.

Method: Due to the limited availability of human lung tissue, standardization of the PCLS method was performed with rat lung tissue. Pulmonary enzymatic activity was found to vary significantly with rat age and rat strain. The Dynamic Organ Culture (DOC) system was superior to well-plates for tissue incubations, while oxygen supply appeared to have a limited impact within the 4h incubation period used here.

Results: The metabolism of a range of phase I and phase II probe substrates was assessed in rat and human lung preparations. Cytochrome P450 (CYP) activity was relatively low in both species, whereas phase II activity appeared to be more significant.

Conclusion: PCLS is a promising tool for the investigation of pulmonary drug metabolism. The data indicates that pulmonary CYP activity is relatively low and that there are significant differences in enzyme activity between rat and human lung.

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用精确肺切片(PCLS)比较大鼠和人肺代谢。

背景:虽然肝脏是药物代谢的主要器官，但肺部也含有药物代谢酶，因此可能有助于药物的消除。在这项研究中，精确切割肺切片(PCLS)技术被标准化，目的是表征和比较大鼠和人的肺部药物代谢活性。方法:由于人肺组织有限，采用大鼠肺组织对PCLS方法进行标准化。肺酶活性随大鼠年龄和品系的变化有显著差异。动态器官培养(DOC)系统在组织培养方面优于孔板，而在这里使用的4小时孵育期间，供氧似乎影响有限。结果:评估了一系列I期和II期探针底物在大鼠和人肺制剂中的代谢。细胞色素P450 (CYP)活性在两个物种中都相对较低，而II期活性似乎更显著。结论:PCLS是研究肺部药物代谢的理想工具。数据表明，肺CYP活性相对较低，大鼠和人肺的酶活性存在显著差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.