Passive Membrane Penetration of the Serotonin Precursor 5-Hydroxytryptophan is Controlled by Its Zwitterion.

Abstract

Species-specific partition coefficients in the octanol/water system were determined for the neurotransmitter serotonin (5-HT) and its precursor 5-hydroxytryptophan (5-HTP). The pH-independent partition coefficients (p) of the individual microspecies were determined by combination of experimentally measured distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. Experimental microscopic partition coefficients for triprotic molecules have only been reported before for thyroxine and its derivatives. The parabolic pH-distribution profile of 5-HT shows the dominance of the lipophilic non-charged microspecies, with a log p of 0.66. However, the most lipophilic non-charged form of 5-HTP, with a log p of 0.31, has no significant contribution to the distribution coefficient at any pH value. Instead, the less lipophilic zwitterionic protonation isomer dominates the distribution in the pH range 2.10-11.11. Although the non-charged microspecies of 5-HTP is 151 times more lipophilic than its zwitterionic protonation isomer, the overwhelming dominance of the zwitterionic form ensures that its contribution to the overall lipophilicity exceeds 1320 times that of the non-charged one. This fact is another counter-example of the widespread belief that passive diffusion into lipophilic media is predominated by the non-charged species. The lipophilicity profile of 5-HT and 5-HTP is depicted in terms of species-specific lipophilicities.