کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8514121 | 1556501 | 2017 | 36 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Understanding the Interplay Between Uptake and Efflux Transporters Within In Vitro Systems in Defining Hepatocellular Drug Concentrations
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کلمات کلیدی
Mrp2Sandwich-cultured hepatocytesBDDCSABTOATPDulbecco’s modified essential mediumBcrpDMEMHBSSCDFITSDPBS1-aminobenzotriazole - 1-آمینوبنزوتریازولCa2+ - Ca2 +DMSO - DMSOHanks balanced salt solution - Hanks محلول نمک را تعویض می کندHepatocytes - hepatocytesSCH - اس اسhepatic transport - انتقال کبدیTransporters - حمل و نقلDimethyl sulfoxide - دیمتیل سولفواکسیدbiliary excretion index - شاخص دفع صفراویdulbecco’s phosphate-buffered saline - فسفات باسیل نمک dulbeccoMethanol - متانولMeOH - مونHepatobiliary disposition - وضعیت بیماری کبدBEI - وقتیbiliary clearance - پاکسازی صفراویHepatic clearance - پاکسازی کبدbreast cancer resistance protein - پروتئین مقاومت به سرطان سینهMultidrug resistance protein 2 - پروتئین مقاومتی چند دارویی 2organic anion-transporting polypeptide - پلی اتیلن حمل و نقل آنیونی آلیCalcium ions - یون کلسیم
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
One of the most holistic in vitro systems for prediction of intracellular drug concentrations is sandwich-cultured hepatocytes (SCH); however, a comprehensive evaluation of the utility of SCH to estimate uptake and biliary clearances and the need for additional kinetic parameters has yet to be carried out. Toward this end, we have selected 9 compounds (rosuvastatin, valsartan, fexofenadine, pravastatin, repaglinide, telmisartan, atorvastatin, saquinavir, and quinidine) to provide a range of physicochemical and hepatic disposition properties. Uptake clearances were determined in SCH and compared with conventional monolayer and suspension hepatocyte systems, previously reported by our laboratory. CLuptake ranged from 1 to 41 μL/min/106 cells in SCH which were significantly lower (1%-10%) compared with the other hepatocyte models. The hepatocyte-to-media unbound concentration ratio (Kpu) has been assessed and ranged 0.7-59, lower compared with other hepatocyte systems (8-280). Estimates of in vitro biliary clearance (CLbile) for 4 drugs were determined and were scaled to predict in vivo values using both intracellular concentration and media drug concentrations. These studies demonstrate that reduced uptake in rat SCH may limit drug access to canalicular efflux transport proteins and highlight the importance of elucidating the interplay between these proteins for accurate prediction of hepatic clearance.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 9, September 2017, Pages 2815-2825
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 9, September 2017, Pages 2815-2825
نویسندگان
Carina Cantrill, J. Brian Houston,