Quantitative structure–permeability relationships at various pH values for neutral and amphoteric drugs and drug-like compounds^$

$ Presented at the 17th International Conference on QSAR in Environmental and Health Sciences (QSAR 2016), 13–17 June 2016, Miami Beach, FL, USA.

Abstract

Human intestinal absorption is a key property for orally administered drugs and is dependent on pH. This study focuses on neutral and amphoteric compounds and their membrane permeabilities across the range of pH values found in the human intestine. The membrane permeability values for 15 neutral and 60 amphoteric compounds at pH 3, 5, 7.4 and 9 were measured using the parallel artificial membrane permeability assay (PAMPA). For each data series the quantitative structure–permeability relationships were developed and analysed. The results show that the membrane permeability of neutral compounds is attributed to a single structural characteristic, the hydrogen bond donor ability. Amphoteric compounds are more complex because of their chemical constitution, and therefore require three-parameter models to describe and predict membrane permeability. Analysis of the models for amphoteric compounds reveals that membrane permeability depends on multiple structural characteristics: the partition coefficient, hydrogen bond properties and the shape of the molecules. In addition to conventional validation strategies, two external compounds (isradipine and omeprazole) were tested and revealed very good agreement of pH profiles between experimental and predicted membrane permeability for all of the developed models. Selected QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.184).

Keywords:

• Membrane permeability
• PAMPA
• pH dependence
• QSAR
• neutral drugs
• amphoteric drugs
• ampholyte

Notes

$ Presented at the 17th International Conference on QSAR in Environmental and Health Sciences (QSAR 2016), 13–17 June 2016, Miami Beach, FL, USA.