TY - JOUR
T1 - Segmental-Dependent Intestinal Drug Permeability
T2 - Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values
AU - Wolk, Omri
AU - Markovic, Milica
AU - Porat, Daniel
AU - Fine-Shamir, Noa
AU - Zur, Moran
AU - Beig, Avital
AU - Dahan, Arik
N1 - Publisher Copyright: © 2019 American Pharmacists Association®
PY - 2019/1/1
Y1 - 2019/1/1
N2 - The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, MW, H-bond count, and Log fu, with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R2 = 0.914), with similar predictability in each SI segment. Log p and Log fu were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and MW. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability.
AB - The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, MW, H-bond count, and Log fu, with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R2 = 0.914), with similar predictability in each SI segment. Log p and Log fu were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and MW. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability.
KW - BCS
KW - in silico predictions
KW - intestinal permeability
KW - oral drug absorption
KW - segmental-dependent permeability
KW - small intestine
UR - http://www.scopus.com/inward/record.url?scp=85054188755&partnerID=8YFLogxK
U2 - 10.1016/j.xphs.2018.07.017
DO - 10.1016/j.xphs.2018.07.017
M3 - Article
C2 - 30055228
SN - 0022-3549
VL - 108
SP - 316
EP - 325
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 1
ER -