Lin, Xuena, Skolnik, Suzanne, Chen, Xiao-Hui and Wang, Jianling (2010) Attenuation of Intestinal Absorption by Major Efflux Transporters: Quantitative tools and strategies using Caco-2 model. Drug Metabolism and Deposition, 39 (2). pp. 265-274. ISSN 0090-9556

Abstract

Efflux transporters expressed in the apical membrane of intestinal enterocytes have been implicated in drug oral absorption. The current study presents a strategy and tools to quantitatively predict efflux impact on oral absorption for new chemical entities (NCEs) in early drug discovery. Sixty-two marketed drugs with human absorption data were evaluated in the Caco-2 bidirectional permeability assay and subjected to specific transporter inhibition. A four-zone graphical model was developed from apparent permeability and efflux ratio to quickly identify compounds whose efflux activity may distinctly influence human absorption. NCEs in “zone 4” will likely have efflux as a barrier for oral absorption and further mechanistic studies are required. The previously described absorption quotient (AQ) was integrated into our data analysis towards a model to project the impact of physicochemical properties on drug absorption. In this way chemistry strategy may be focused on passive permeability or efflux activity or both. We introduced a new substrate classification parameter, transporter substrate index (TSI). More quantitative than efflux ratio and more widely applicable than AQ, TSI considered both in vitro and in vivo outcomes. Its application ranged from addressing the challenge of overlapping substrate specificity to projecting the role of transporter(s) on exposure or potential DDI risk.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Keywords:	efflux, transporter, permeability, absorption, Caco-2,
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/2929