کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2507171 1557544 2006 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Evaluation of an integrated in vitro–in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی علوم دارویی
پیش نمایش صفحه اول مقاله
Evaluation of an integrated in vitro–in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability
چکیده انگلیسی

PK express module is a physiologically based model of first pass metabolism, which integrates in vitro data with an in silico physiologically based pharmacokinetic (PBPK) model to predict human bioavailability (FH). There are three required inputs: FDp (Fraction dose absorbed, final parameter from iDEA absorption module), protein binding (fu) and disappearance kinetics in human hepatocytes. Caco-2 permeability, aqueous solubility (at multiple pH's), estimated dose and chemical structure are inputs required for the estimation of FDp ( Norris et al., 2000 and Stoner et al., 2004) and were determined for all compounds in our laboratory or obtained from literature. Protein binding data was collected from literature references and/or Pfizer database. Human hepatocyte data was generated in-house using an automated human hepatocyte method (using Tecan Genesis™ Workstation) as described previously (Reddy et al., 2004). Sixteen compounds (commercial and Pfizer compounds) were chosen to evaluate the PK express model and the bioavailability predicted from the module was compared with known clinical endpoints. For majority of the 16 compounds (approximately 80%), the PK express model FH values were comparable to the known human bioavailability (FH) (within 23.7 units of the known human (true) F, except for PF 3, PF 4, PF 6). In conclusion, the PK express model integrates a number of key readily available discovery parameters and provides estimates of human performance by integrating in silico and experimental variables built on a physiological based pharmacokinetic model. Information from this model in conjunction with other ADME data (e.g., P450 inhibition) will enable progression of most promising compounds for further in vivo PK and/or efficacy studies.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: International Journal of Pharmaceutics - Volume 308, Issues 1–2, 3 February 2006, Pages 133–139
نویسندگان
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