کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2478870 1113408 2014 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Development of Mice Exhibiting Hepatic Microsomal Activity of Human CYP3A4 Comparable to That in Human Liver Microsomes by Intravenous Administration of an Adenovirus Vector Expressing Human CYP3A4
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Development of Mice Exhibiting Hepatic Microsomal Activity of Human CYP3A4 Comparable to That in Human Liver Microsomes by Intravenous Administration of an Adenovirus Vector Expressing Human CYP3A4
چکیده انگلیسی

Summary:Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the pharmacokinetic and safety profiles of drugs. However, it is difficult to properly predict the pharmacokinetics and hepatotoxicity of drugs in humans using data from experimental animals, because the catalytic activities of CYP3A4 and other drug-metabolizing enzymes differ between human and animal organs. In order to easily generate an animal model for proper evaluation of human CYP3A4-mediated drug metabolism, we developed a human CYP3A4- expressing adenovirus (Ad) vector based on our novel Ad vector exhibiting significantly lower hepatotoxicity (Ad-E4-122aT-hCYP3A4). Intravenous administration of Ad-E4-122aT-hCYP3A4 at a dose of 2 × 1011 virus particles/mouse produced a mouse exhibiting human CYP3A4 activity at a level similar to that in the human liver, as shown in the dexamethasone metabolic experiment using liver microsomes. The area under the curve (AUC) of 6/βSOHD was 2.7-fold higher in the Ad-E4-122aT-hCYP3A4-administered mice, compared with the mice receiving a control Ad vector. This Ad vector-expressing human CYP3A4 would thus be a powerful tool for evaluating human CYP3A4-mediated drug metabolism in the livers of experimental animals.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Drug Metabolism and Pharmacokinetics - Volume 29, Issue 4, 2014, Pages 296-304