Computational Prediction of Oral Drug Absorption Based on Absorption Rate Constants in Humans

Abstract

Models for predicting oral drug absorption kinetics were developed by correlating absorption rate constants in humans (K(a)) with computational molecular descriptors. The K(a) values of a set of 22 passively absorbed drugs were derived from human plasma time-concentration profiles using a deconvolution approach. The K(a) values correlated well with experimental values of fraction of dose absorbed in humans (FA), better than the values of human jejunal permeability (P(eff)) which have previously been used to assess the in vivo absorption kinetics of drugs. The relationships between the K(a) values of the 22 structurally diverse drugs and computational molecular descriptors were established with PLS analysis. The analysis showed that the most important parameters describing log K(a) were polar surface area (PSA), number of hydrogen bond donors (HBD), and log D at a physiologically relevant pH. Combining log D at pH 6.0 with PSA or HBD resulted in models with Q(2) and R(2) values ranging from 0.74 to 0.76. An external data set of 169 compounds demonstrated that the models were able to predict K(a) values that correlated well with experimental FA values. Thus, it was shown that, using a combination of only two computational molecular descriptors, it is possible to predict with good accuracy the K(a) value for a new drug candidate.

In Silico Prediction of Drug Permeability Across Buccal Mucosa

“…The best model reported by these researchers consisted of logD 5.5 , PSA and HBD. Another study by Linnankoski et al also revealed that HBD (and not HBA) was among the most important parameters describing the oral absorption rate constant (39). The reason for the importance of HBD in permeability might be the predominant presence of hydrogen bond acceptors in the head group regions of membrane bilayer lipids (11).…”

“…However, in addition to these descriptors, HBD and nRotB were also found to be important in predicting buccal permeability. Previous studies have demonstrated that a greater hydrogen bonding capability, especially, the number of hydrogen bond donors, of a molecule decreases its permeability probably due to increased interactions with the lipid bilayer (14,39). In an earlier study by Winiwarter et al, the human jejunal permeability values of 13 passively absorbed compounds were correlated with several physicochemical descriptors using partial least squares (PLS) (40).…”

Physiologically Based Pharmacokinetics of Matrine in the Rat after Oral Administration of Pure Chemical and ACAPHA

“…This is probably due to the different water solubility of pure matrine and crude matrine. Linnankoski et al (2006) have shown that drug absorption is determined mainly by the dissolution rate in the gastrointestinal fluids. Because pure matrine dissolves in water readily, it is rapidly absorbed by the rat.…”

Prediction of the Corneal Permeability of Drug-Like Compounds

“…Previously, it has been reported that the absorption of drug-like compounds in the human intestine can be predicted as accurately with computational models as with in vitro experiments (7). Even though quantitative structure-property relationship (QSPR) models for transdermal and intestinal absorption of drugs have been constructed (8)(9)(10), QSPR models for the corneal permeability are still at an elementary level. Some computational models for predicting the corneal permeability have been developed (2,(11)(12)(13)(14), but so many of these models have been constructed for a small set of similar compounds (2,13), and the models are thus not applicable to a broader variety of molecules.…”