title: Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters.
abstract: 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.
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences Hőgyes E. u. 9., H-1092 Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Mazák
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, Research Group of Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences Hőgyes E. u. 9., H-1092 Budapest, Hungary. Electronic address: noszal.bela@pharma.semmelweis-univ.hu.
authors.forename: Béla
authors.initials: B
authors.lastname: Noszál
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology; D000818:Animals; D001685:Biological Factors / Q000032:analysis*; D001688:Biological Products / Q000032:analysis* / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D004364:Pharmaceutical Preparations / Q000032:analysis*; D013045:Species Specificity
chemical_list: D001685:Biological Factors; D001688:Biological Products; D004364:Pharmaceutical Preparations
keywords: Acid-base chemistry; Amphoteric compounds; Concentration of microspecies; Lipophilicity; Membrane penetration; Microspeciation; Partition coefficient; Redox equilibria; Solubility; Species-specific physico-chemical properties; Zwitterions