کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2478792 1113403 2014 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Evaluation of Human Hepatocytes Cultured by Three-dimensional Spheroid Systems for Drug Metabolism
ترجمه فارسی عنوان
بررسی هپاتوسیت های انسانی که به وسیله سیستم های اسپروئیدی سه بعدی برای متابولیسم مواد مخدر تولید می شوند
کلمات کلیدی
هپاتوسیت انسان اسفروئید، آنزیم های متابولیکی، متابولیسم متوالی بیوت تبدیل
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
چکیده انگلیسی

Summary:We investigated the utility of three-dimensional (3D) spheroid cultures of human hepatocytes in discovering drug metabolites. Metabolites of acetaminophen, diclofenac, lamotrigine, midazolam, propranolol and salbutamol were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS) to measure enzyme activities in this system cultured for 2 and 7 days. Sequential metabolic reactions by Phase I and then Phase II enzymes were found in diclofenac [CYP2C9 and UDP-glucuronyltransferases (UGTs)], midazolam (CYP3A4 and UGTs) and propranolol (CYP1A2/2D6 and UGTs). Moreover, lamotrigine and salbutamol were metabolized to lamotrigine-N-glucuronide and salbutamol 4-O-sulfate, respectively. These metabolites, which are human specific, could be observed in clinical studies, but not in conventional hepatic culture systems as in previous reports. Acetaminophen was metabolized to glucuronide and sulfate conjugates, and N-acetyl-p-benzo-quinoneimine (NAPQI) and its metabolites were not observed. In addition, mRNA of drug-metabolism enzymes [CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, UGT1A1, UGT2B7, sulfotransferase 1A1 (SULT1A1) and glutathione S-transferase pi 1 (GSTP1)], which were measured by qRT-PCR, were expressed in the human hepatocyte spheroids. In conclusion, these results suggest that human hepatocyte spheroids are useful in discovering drug metabolites.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Drug Metabolism and Pharmacokinetics - Volume 29, Issue 5, 2014, Pages 373–378
نویسندگان
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