Ionization-specific analysis of human intestinal absorption.
This study presents a mechanistic QSAR analysis of human intestinal absorption of drugs and drug-like compounds using a data set of 567 %HIA values. Experimental data represent passive diffusion across intestinal membranes, and are considered to be reasonably free of carrier-mediated transport or other unwanted effects. A nonlinear model was developed relating %HIA to physicochemical properties of drugs (lipophilicity, ionization, hydrogen bonding, and molecular size). The model describes ion-specific intestinal permeability of drugs by both transcellular and paracellular routes, and also accounts for unstirred water layer effects. The obtained model was validated on two external data sets consisting of in vivo human jejunal permeability coefficients (P(eff)) and absorption rate constants (K(a)). Validation results demonstrate good predictive power of the model (RMSE = 0.35-0.45 log units for log K(a) and log P(eff)). High prediction accuracy together with clear physicochemical interpretation (log P, pK(a)) makes this model particularly suitable for use in property-based drug design.
Reytek Limited, 11C Rothsay Road, Bedford MK40 3PP, UK.
Derek P
DP
Reynolds
Kiril
K
Lanevskij
Pranas
P
Japertas
Remigijus
R
Didziapetris
Alanas
A
Petrauskas
D055598:Chemical Phenomena; D004058:Diffusion; D004573:Electrolytes / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D008956:Models, Chemical; D015233:Models, Statistical; D008970:Molecular Weight; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012984:Software; D055672:Static Electricity
D004573:Electrolytes; D004364:Pharmaceutical Preparations