In Vitro Studies on Potential Mechanisms of Absorption Enhancement by Hvdroxybenzoates

Various groups of workers (e.g. Nishihata et al 1980a,81ab,82ab) have demonstrated that derivatives of salicylic acid can enhance the absorption of normally poorly absorbed drugs. The work described in this thesis is an investigation into the possible mechanisms by which these adjuvants act. Various physicochemical parameters of the adjuvants were determined and related by linear, multiple linear and multiple non-linear regression analyses to their biological activities. No significant correlations were obtained between the physicochemical parameters of the adjuvants and their abilities to enhance drug absorption, or their own absorption, in the basic region. General trends were observed between adjuvant absorption in the acidic region and various physicochemical parameters or combinations of parameters. These findings supported the ideas put forward by Nishihata et al. (1981a) that adjuvant absorption in this region may be regulated by their lipophilicity.

Adjuvant fluxes alone and in the presence of drug, were determined across various model membranes supported in Rotating Diffusion Cell (RDC) systems. Systems studied incorporating both adjuvant and drug did not mimic the in vivo system. Measurements of adjuvant flux alone, across simple lipid membranes, produced significant correlations with adjuvant absorption in the acidic region, but no correlations were found for adjuvant absorption in the basic region.

Kinetic analysis of the adjuvant flux data and comparison with adjuvant absorption in the acidic region suggested that interfacial transfer is the rate limiting step in their absorption. This finding supports recent evidence that interfacial transfer may be the rate limiting stage in a number of biological processes.

Overall, no conclusive evidence was found concerning the mechanism by which adjuvants enhance drug absorption or are themselves well absorbed in the basic region. Several possibilities related to lipophilic mechanisms would appear to have been discounted by these findings.