Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

The pharmacokinetic and pharmacodynamic behaviour of drugs and the interacting biomolecules are highly influenced by their species-specific physico-chemical properties. The first of such bio-relevant, structure-dependent properties were the species-specific acid-base constants and the co-dependent concentrations, but the past decade brought significant advances to previously uncharted territories, including the experimental determination of species-specific partition coefficients, solubilities and redox equilibrium constants. This review gives an overview of the types and definitions of species-specific physico-chemical and analytical properties. We survey the pertinent literature, the fundamental relationships, and summarize some of our recent work that enabled the determination of species-specific partition coefficients for coexisting, inseparable protonation isomers and pH-independent, microscopic redox equilibrium constants. The thorough insight provided by these species-specific properties improves our understanding of the submolecular mechanism of pharmacokinetic processes. As a result, there are some pieces of clear-cut evidence of practical significance. A few of them are as follows: -passive diffusion into lipophilic media is not necessarily predominated by the non-charged species, contrary to the widespread misbelief. -the reactive microspecies in structure-controlled, highly specific biochemical reactions is not necessarily the major one. -a preventive defence system against oxidative stress can be based upon thiol-disulfide equilibria of custom-tailored redox potentials. (C) 2016 Published by Elsevier B.V.