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-three 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. To interpret mechanistic results, we introduced a new quantitative substrate classification parameter, transporter substrate index (TSI). TSI allowed more flexibility and 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. The potential impact of efflux transporters associated with physicochemical properties on drug absorption was discussed in the context of TSI and also previously reported absorption quotient (AQ). In this way chemistry strategy may be differentially focused on passive permeability or efflux activity or both.
- ABC transporters
- absorption
- active transport
- drug absorption
- drug transport
- intestinal transport
- membrane permeability
- multi-drug resistance
- permeability
- transporters
- Received May 21, 2010.
- Accepted November 4, 2010.
- The American Society for Pharmacology and Experimental Therapeutics