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

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 r(2) > 0.8 for pH 3 and pH 5. For basic compounds, the best (r(2) > 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 ).

Real-Time Parallel Artificial Membrane Permeability Assay Based on Supramolecular Fluorescent Artificial Receptors

“…For instance, the permeability coefficients (log P e ) of indole and coumarin are reported as −4.50 and −4.55, respectively, which are considered fast (Fujikawa et al, 2007 ). In contrast, doxepin, whose permeability coefficient is < −6 in acidic solutions (which matches our experimental condition for using doxepin hydrochloride in the donor well), is categorized as slow permeation (Oja and Maran, 2015 ). Meanwhile, the performance of l -tryptophanamide is moderate to slow with a permeability coefficient of −5.56 (Fujikawa et al, 2007 ).…”

“…The thickness of the unstirred water layer, for example, is a critical parameter, especially for large drug molecules; in some circumstances, it can be a rate-limiting step (Wohnsland and Faller, 2001 ; Nielsen and Avdeef, 2004 ). The pH of the drug solution is another important factor, as the neutral form of a compound regularly has a larger permeability than the ionic one (Oja and Maran, 2015 ). Besides, the in vivo absorptive sink condition (e.g., a pH gradient at the two sides of the membrane, blood flow, and serum proteins) has also been considered, which led to the development of the double-sink PAMPA method, as a variant (Avdeef, 2003 ; Avdeef et al, 2004 ).…”

In Silico Prediction of PAMPA Effective Permeability Using a Two-QSAR Approach

“…However, PAMPA permeability is sensitive to the assay conditions (vide supra). To warrant data consistency and to minimize the variations in assay conditions among different data sources [34,38,39,40,41,42,51,55,75,77,78,79,80], only those molecules assayed by Oja and Maran [39,41,42] were selected in this study since they generated the largest quantity of data. If there were two or more available efflux ratio data for a given compound and in close range, the average values were then taken in order to warrant better consistency.…”

“…As such, in silico approaches play an increasing role in ADME/Tox profiling [27]. In fact, numerous qualitative structure–activity relationship (QSAR) models have been developed to predict PAMPA permeability [7,23,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47].…”

Validating ADME QSAR Models Using Marketed Drugs

“…Only a limited number of studies reported models for PAMPA permeability in literature. 31–35 Most studies either use a different kind of assay to measure PAMPA permeability or use small datasets comprising a few hundred compounds. Searching by keyword “PAMPA” resulted in a total of 935 assay records and 1015 measurements on ChEMBL.…”