کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8514498 | 1556507 | 2017 | 37 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey
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موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin-Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein-cannulated cynomolgus monkey. In vitro-in vivo extrapolation (IVIVE) of FaFg was developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFg was observed for cynomolgus monkey with R2 of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFg for CES substrates with high confidence.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 3, March 2017, Pages 898-905
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 3, March 2017, Pages 898-905
نویسندگان
Patrick E. Trapa, Kevin Beaumont, Karen Atkinson, Heather Eng, Amanda King-Ahmad, Dennis O. Scott, Tristan S. Maurer, Li Di,