کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2484288 | 1114305 | 2016 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Hepatic Clearance Prediction of Nine Human Immunodeficiency Virus Protease Inhibitors in Rat
ترجمه فارسی عنوان
پیش بینی کالری کبدی از مهارکننده های پروتئاز ویروس نقص ایمنی بدن انسان در موش صحرایی
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کلمات کلیدی
FBSHEPESIVIVEin vitro–in vivo extrapolationin vitro/in vivo correlations (IVIVC)drug metabolizing enzymes - آنزیم های متابولیسم داروhepatic transport - انتقال کبدیHIV/AIDS - ایدز/ویروس نقص ایمنیDrug transport - حمل مواد مخدرTransporters - حمل و نقلfetal bovine serum - سرم جنین گاوHepatic metabolism - متابولیسم کبدیProtease inhibitor - مهارکننده پروتئازHIV - ویروس نقص ایمنی انسانی human immunodeficiency virus - ویروس نقص ایمنی انسانیHepatic clearance - پاکسازی کبد
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
چکیده انگلیسی
This study aimed to determine the rate-limiting step in the overall hepatic clearance of the marketed human immunodeficiency virus (HIV) protease inhibitors (PI) in rats by predicting the experimentally determined hepatic in vivo clearance of these drugs based on in vitro clearance values for uptake and/or metabolism. In vitro uptake and metabolic clearance values were determined in suspended rat hepatocytes and rat liver microsomes, respectively. In vivo hepatic clearance was determined after intravenous bolus administration in rats. Excellent in vitro-in vivo correlation (IVIVC; R2 = 0.80) was observed when metabolic intrinsic Cl values were used, which were determined in vitro at a single concentration corresponding to the blood concentration observed in rats in vivo at the mean residence time. On the contrary, poor IVIVC was observed when in vitro metabolic Cl values based on full Michaelis-Menten profiles were used. In addition, the use of uptake Cl values or a combination of both uptake and metabolic clearance data led to poor predictions of in vivo clearance. Although our findings indicate a key role for metabolism in the hepatic clearance of several HIV PI in rats, subsequent simulations revealed that inhibition of hepatic uptake can lead to altered hepatic clearance for several of these drugs.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 2, February 2016, Pages 846-853
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 2, February 2016, Pages 846-853
نویسندگان
Tom De Bruyn, Patrick F. Augustijns, Pieter P. Annaert,