Structure‐based prediction of human intestinal membrane permeability for rapid in silico BCS classification

Abstract

Human effective intestinal membrane permeability (Peff) is one of the two important indicators for drug classification according to the Biopharmaceutical Classification System (BCS), and contributes greatly to the performance of oral drug absorption. Here, a structure-based in silico predictive model of Peff was developed successfully to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure-Peff relationship for 30 drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal probability-probability plot and the Williams plot. For the entire data set, the R² and adjusted R² values were 0.782 and 0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for the 102 tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for 57 drugs that have been classified according to the BCS, and 72% of drugs could be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stages of drug discovery.

Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies

“…S5 (ESM), the non-toxic concentration for ergotamin(in)e was selected at 10 μg/mL and lower. Human studies have shown overall low oral bioavailability of ergotamine [45,46], and it has been classified to be a BCS III compound, meaning a low-permeability compound [47]. Therefore, we used the highest non-toxic concentration possible for the ergotamin(in)e permeability experiments (10 μg/mL).…”

Entropy and Polarity Control the Partition and Transportation of Drug-like Molecules in Biological Membrane

“…Extensive studies have been done to explore the transportation of drug-like compounds with computations, which provide valuable insights into the details at atomic level that cannot be accessed by experiments 17 – 20 . Among different descriptors for characterizing the permeability of drug-like compounds 21 – 23 , the partition coefficient (log P ) is the most commonly used one. Log P is defined as the logarithm of the ratio of compounds dissolved in lipid bilayers and the buffer water of a two-compartment system under equilibrium conditions.…”

Integrating theoretical and experimental permeability estimations for provisional biopharmaceutical classification: Application to the WHO essential medicines

“…Finally, among the most relevant high‐throughput methods for studying intestinal permeability and the oral absorption of drugs are the in silico approaches. Several quantitative structure–property relationships (QSPR) have been proposed for the prediction of human intestinal absorption, membrane permeability as well as for BCS classification (Kasim et al, ; Newby, Freitas, & Ghafourian, ; Pham‐The, González‐Álvarez et al, ; Pham‐The et al, ; Sun et al, ; Wolk, Agbaria, & Dahan, ). In silico models are inexpensive tools with a high‐throughput capacity, but their accuracy is limited by the quality of the raw in vivo data upon which they are based, the statistical approach and the kind of molecular descriptors used in the models.…”