Abstract
Profiling blood-brain barrier permeability of bioactive molecule is an important issue in early drug development, being a part of the optimization process of a compound's physicochemical properties, and hence pharmacokinetic profile. The study aimed to develop and optimize a new in vitro method for assessment of the compound's brain penetration. The tool is proposed as an alternative to the PAMPA-BBB (Parallel Artificial Membrane Permeability Assay for Blood-Brain Barrier) and based on a capillary electrochromatography (CEC) technique. It utilizes liposomes as structural substitutes of biological membranes, which are used as a capillary inner wall coating material. Following optimization of analysis conditions, migration times for a set of 25 reference drugs (mainly non-ionized in pH 7.4) were examined in a liposome coated capillary. On that basis, the retention factor (log k) was determined for each reference drug. Obtained log k values and experimentally received reference permeability parameters: log BB (in vivo data) and log Pe (PAMPA-BBB data) were compared with one another. Correlation coefficients were calculated, giving comparable results for CEC log k/log BB and analogical PAMPA-BBB log Pe/log BB analyses. Approximate ranges of log k for the central nervous system (CNS) permeable (CNS(+)) and non-permeable (CNS(−)) drugs were established.
Highlights
The drug development process requires both the evaluation of the pharmacological activity of a newly synthesized molecule and the optimization of its pharmacokinetic profile, defined mostly by physicochemical properties
After coating the capillary with phospholipid components (POPC/PS) liposomes, 25 compounds were analyzed and their log k parameters were calculated on the basis of their migration times, according to the Equation (2), log k = log tR tEOF
25 marketed drugs were used as references for the new, permeability prediction capillary electrochromatography (CEC) method development
Summary
The drug development process requires both the evaluation of the pharmacological activity of a newly synthesized molecule and the optimization of its pharmacokinetic profile, defined mostly by physicochemical properties. Optimal physicochemical properties determine a compound's permeability through biological membranes, affecting all ADMET processes (absorption, distribution, metabolism, excretion, and toxicity). Interaction between a bioactive molecule and the biological membrane is essential in terms of both, its absorption from the gastrointestinal tract and its penetration through the other barriers in the body, including the important blood-brain barrier (BBB). For potential central nervous system (CNS) drugs, profiling their BBB permeability is crucial for the further development of these molecules. A compound that lacks optimal physicochemical properties determining brain penetration is usually disqualified, even despite the strong in vitro activity toward its biological target. Brain penetration is important for drugs acting within the CNS; it is essential for peripherally active compounds due to their possible adverse brain-related effects
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