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 the impact of efflux 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 ratios to quickly identify compounds whose efflux activity may distinctly influence human absorption. NCEs in “zone 4” will probably 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 drug-drug interaction risk. The potential impact of efflux transporters associated with physicochemical properties on drug absorption is discussed in the context of TSI and also the previously reported absorption quotient. In this way, the chemistry strategy may be differentially focused on passive permeability or efflux activity or both.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034629.
-
ABBREVIATIONS:
- GI
- gastrointestinal tract
- P-gp
- p-glycoprotein
- MRP2
- multidrug resistance protein 2
- BCRP/bcrp
- breast cancer resistance protein
- MDR/mdr
- multidrug resistance
- DDI
- drug-drug interaction
- ER
- efflux ratio
- NCE
- new chemical entity
- TSI
- transporter substrate index
- AQ
- absorption quotient
- LY335979
- (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6yl)-α-((5-quinoloyloxy)methyl)-1-piperazine ethanol
- MK571
- 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
- Ko143
- [3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester]
- A
- apical
- B
- basolateral
- FA
- fraction absorbed
- MDCK
- Madin-Darby canine kidney
- AUC
- area under the curve
- KO
- (gene) knockout
- WT
- wild type
- BDDCS
- Biopharmaceutics Drug Disposition Classification System
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide.
- Received May 21, 2010.
- Accepted November 4, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|