Percutaneous penetration of nicotinates: in vivo and in vitro measurements.

ABSTRACT

The relationship between chemical structure and percutaneous absorption has been explored with nicotinic acid and its methyl, ethyl, hexyl, and benzyl esters. Skin penetration has been measured in vitro across hairless mouse skin and in vivo in humans. In vitro, methyl and ethyl nicotinates (when applied in acetone) were delivered into skin such that the stratum corneum barrier was effectively bypassed. The lipophilic esters, on the other hand, were not solubilized in this way and penetrated more slowly. Nicotinic acid penetrated poorly, yielding essentially zero-order skin transport kinetics. Tape-stripping experiments, in which penetration was monitored across skin with no stratum corneum, confirmed these observations. In vivo absorption of the esters was determined from the urinary excretion of total radioactivity following topical administration of 14C-labeled penetrant. Kinetic analysis of the data yielded rate constants, the ratio of which correlated acceptably with the penetrant octanol-water partition coefficient (K). The dependence of the rate constants on K was interpreted in terms of the relative affinity of the substrate for the stratum corneum compared with the viable tissue; the relationship agrees well with a previous evaluation involving structurally unrelated molecules.