Quantitative structure–permeability relationships at various pH values for acidic and basic drugs and drug-like compounds

^$Presented at the 8th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, 21–25 June 2015, Chios, Greece.

Abstract

Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r² > 0.8 for pH 3 and pH 5. For basic compounds, the best (r² > 0.7) structure–permeability relationships are obtained with the octanol–water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.166).

Keywords:

• membrane permeability
• PAMPA
• pH dependence
• QSAR
• acidic drugs
• basic drugs

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

^$ Presented at the 8th International Symposium on Computational Methods in Toxicology and Pharmacology Integrating Internet Resources, CMTPI-2015, 21–25 June 2015, Chios, Greece.

Additional information

Funding

The authors thank the Estonian Ministry for Education and Research [grant number IUT34-14], Estonian Research Council [grant number 7709] and European Union Regional Development Fund [grant number 3.2.1201.13-0021].