Absorption-partition relationships for true homologous series of xenobiotics as a possible approach to study mechanisms of surfactants in absorption. I. Aromatic amines in rat colon

Abstract

The relationships between absorption rate constants found in rat colon and lipophilicity are investigated for a homologous series of xenobiotics (4-alkylanilines) in the presence of a non-ionic surfactant, polysorbate 80, at its CMC and at concentrations clearly supramicellar. The results are compared with those obtained in the absence of surfactant in order to substantiate the effects of this additive in the absorption of xenobiotics. At CMC, the surfactant seems to have two main effects: first, it acts as a modifier of the colonic adsorbent membrane permeability, and second, it nullifies the limiting effect on absorption which is achieved, in the absence of surfactant, by the aqueous stagnant diffusion layer adjacent to the membrane. Due to these effects a direct linear, double-logarithmic correlation is found between absorption rate constants (k 0) and partition parameters instead of the hyperbolic-type correlation which is obtained in the absence of surfactant; the more relevant consequence is a significantly enhanced absorption rate constant for highly hydrophilic and highly lipophilic compounds of the series. This behaviour can be explained by a rearranged diffusional absorption model devoid of any limiting step. At supramicellar concentrations, the solubilization of compounds decreases their absorption rate constants relative to that found at CMC, this effect being more marked as the surfactant concentration and the solute lipophilicity increase. The correlation between absorption rate constants ( k s ) and partition parameters becomes bilinear, with a left branch parallel to the k 0 line. This behaviour is explained by the absorption kinetics of the free amine fraction, k s / k 0, as well as with the aid of some partition principles. In the light of this approach a global picture on the influence of the surfactant on drug absorption is obtained whose features are discussed.