Yilmaz Yildiz, Williams Gareth, Walles Markus, Manevski Nenad, Krähenbühl Stephan, Camenisch Gian
Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Clinical Pharmacology and Toxicology, University Hospital, Basel, Switzerland.
Drug Metab Lett. 2019;13(1):53-63. doi: 10.2174/1872312812666181022114622.
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.
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.
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.
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.
尽管肝脏是药物代谢的主要器官，但肺中也含有药物代谢酶，因此可能有助于药物的消除。在本研究中，对精密肺切片（PCLS）技术进行了标准化，旨在表征和比较大鼠和人类的肺药物代谢活性。
由于人类肺组织的可用性有限，使用大鼠肺组织对PCLS方法进行了标准化。发现肺酶活性随大鼠年龄和品系的不同而有显著差异。动态器官培养（DOC）系统在组织孵育方面优于微孔板，而在此处使用的4小时孵育期内，氧气供应似乎影响有限。
在大鼠和人类肺制剂中评估了一系列I相和II相探针底物的代谢情况。两种物种的细胞色素P450（CYP）活性相对较低，而II相活性似乎更为显著。
PCLS是研究肺药物代谢的一种有前途的工具。数据表明，肺CYP活性相对较低，大鼠和人类肺之间的酶活性存在显著差异。
