Zwitterions Can Be Predominant in Membrane Penetration of Drugs: Experimental Proof

Abstract

The complete set of species-specific partition coefficients was determined, and the predominant contribution of zwitterionic species to the overall lipophilicity was experimentally proven for the first time. The compounds studied were the amphoteric eburnane alkaloid cis- and trans-apovincaminic acids of therapeutic interest. Partition of the individual microspecies was mimicked by model compounds of the closest possible similarity, and then correction factors were determined and introduced. The noncharged microspecies of the cis-epimer is 30 900 times as lipophilic as its zwitterionic protonation isomer, while the analogous ratio for the trans-epimer is around 15 800. Due to the overwhelming dominance of the zwitterionic form, however, its contribution to the overall lipophilicity exceeds 8 and 5 times that of the noncharged form for the two epimers, respectively. The lipophilicity profile of these zwitterionic compounds is expressed, calculated, and depicted in terms of species-specific lipophilicities over the entire pH range.