PMID: 20629632Jul 16, 2010Paper

Impact of input parameters on the prediction of hepatic plasma clearance using the well-stirred model

Current Drug Metabolism
Hong WanAntonio Llinàs

Abstract

The in vitro metabolic stability assays are indispensable for screening the metabolic liability of new chemical entities (NCEs) in drug discovery. Intrinsic clearance (CL(int)) values from liver microsomes and/or hepatocytes are frequently used to assess metabolic stability as well as to quantitatively predict in vivo hepatic plasma clearance (CL(H)). An often used approximation is the so called well-stirred model which has gained widespread use. The applications of the well-stirred model are typically dependent on several measured parameters and hence with potential for error-propagation. Despite widespread use, it was recently suggested that the well-stirred model in some circumstances has been misused for in vitro in vivo extrapolation (IVIVE). In this work, we follow up that discussion and present a retrospective analysis of IVIVE for hepatic clearance prediction from in vitro metabolic stability data. We focus on the impact of input parameters on the well stirred model; in particular comparing "reference model" (with all experimentally determined values as input parameters) versus simplified models (with incomplete input parameters in the models). Based on a systematic comparative analysis and model comparison using datase...Continue Reading

Citations

Jul 6, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Kati-Sisko VellonenArto Urtti
Jul 26, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C DesbansA-L Ungell
Feb 25, 2015·Journal of Computer-aided Molecular Design·Ignacio AliagasS Cyrus Khojasteh
Aug 12, 2016·Clinical Pharmacokinetics·Elisa A M CalvierCatherijne A J Knibbe
Jan 25, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Xin LiLianshan Zhang
May 31, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christiane K FæsteSilvio Uhlig
Jul 2, 2019·Acta Pharmaceutica : a Quarterly Journal of Croatian Pharmaceutical Society and Slovenian Pharmaceutical Society, Dealing with All Branches of Pharmacy and Allied Sciences·Karolina SłoczyńskaElżbieta Pękala

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