کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10162773 | 1114359 | 2012 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Evaluation of Hepatic Clearance Prediction Using In Vitro Data: Emphasis on Fraction Unbound in Plasma and Drug Ionisation Using a Database of 107 Drugs
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
Underprediction of in vivo intrinsic clearance (CLint) of unbound drug from human hepatic in vitro systems using physiological extrapolation methodology is accepted as a common outcome. Poulin et al. (2012. J Pharm Sci 101:838-851) recently proposed an approach involving determination of effective fraction unbound in plasma (fup) based on albumin-facilitated hepatic uptake of acidic/neutral drugs which improved prediction accuracy and precision for 25 drugs highly bound to plasma proteins. This approach includes correction of unbound drug according to the ionisation fraction either side of the plasma membrane based on pH difference. Here, we assessed the proposed method using a larger database of predictions of CLint for 107 drugs involving hepatocytes (89 drugs) and microsomes (64 drugs). The proposed method was similarly effective in minimising average prediction bias (to within twofold), unlike the conventional fup correction method. However, precision was similar between methods and there was no evidence in the larger database that prediction bias was associated with fup. Prediction bias for hepatocytes was clearance dependent by either method, indicating important sources of bias from in vitro methodology. Therefore, to progress beyond empirical correction of bias, there is further need of mechanistic elucidation to improve prediction methodology.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 101, Issue 8, August 2012, Pages 2645-2652
Journal: Journal of Pharmaceutical Sciences - Volume 101, Issue 8, August 2012, Pages 2645-2652
نویسندگان
David Hallifax, J. Brian Houston,