TY - JOUR
T1 - Predicting phenolic acid absorption in Caco-2 cells
T2 - A theoretical permeability model and mechanistic study
AU - Farrell, Tracy L.
AU - Poquet, Laure
AU - Dew, Tristan P.
AU - Barber, Stuart
AU - Williamson, Gary
PY - 2012/2/1
Y1 - 2012/2/1
N2 - There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a′, β′, and b′ with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R
2 = 0.93) and predicted reasonably well (R
2 = 0.86) the experimental apparent permeability coefficient (P
app) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the P
app value from the predicted transcellular permeability (P
app
trans) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.
AB - There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a′, β′, and b′ with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R
2 = 0.93) and predicted reasonably well (R
2 = 0.86) the experimental apparent permeability coefficient (P
app) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the P
app value from the predicted transcellular permeability (P
app
trans) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.
UR - http://www.scopus.com/inward/record.url?scp=84856016533&partnerID=8YFLogxK
U2 - 10.1124/dmd.111.041665
DO - 10.1124/dmd.111.041665
M3 - Article
C2 - 22096083
AN - SCOPUS:84856016533
SN - 0090-9556
VL - 40
SP - 397
EP - 406
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 2
ER -