Gastrointestinal absorption of model compounds and free fatty acids.

Abstract

The n-alkanol and n-alkanoic acid homologs, salicylic acid and prostaglandin E$\sb2$ were employed as model permeants to characterize the gastric mucosa of the rat animal model. The in situ modified Doluisio perfusion technique was applied to follow the disappearance kinetics in the stomach. The degree of agitation of the bulk luminal fluid influenced the rate of absorption of salicylic acid at low pH. The weak acids showed sigmoidal-shaped, absorption versus pH curves in which, among the n-alkanoic acids, there was a rightward displacement of the curves with increasing lipophilicity. Whereas diffusion across the aqueous boundary layer became the rate-limiting step for the highly lipophilic compounds, permeation across the aqueous pores became the rate-determining step for the small molecular weight, hydrophilic n-alkanols and weak acids in the anionic state. The interrelationships of lipophilicity, pH, pK$\sb{\rm a}$, molecular size, aqueous boundary layer and membrane permeation indicate that the gastric mucosa is similar to the jejunal mucosa in terms of passive drug absorption and could be operationally regarded as a biomembrane consisting of parallel lipoidal and aqueous pore pathways. There are indications that the lipoidal pathway of the stomach mucosal membrane is less lipophilic than that of the jejunum. The intestinal absorption of a set of long-chain fatty acids, comprised of lauric (C$\sb{12}$), myristic (C$\sb{14}$) and palmitic (C$\sb{16}$) acids, was studied by following their disappearance kinetics via the in situ modified Doluisio perfusion and steady-state flow-through perfusion methods in isolated jejunal segments of the rat. The studies were aimed at understanding the role of molecular association on membrane absorption over a wide range of concentrations, principally at pH 6.0 and 7.5. It was found that C$\sb{12}$ and C$\sb{14}$ fatty acids exhibited aqueous boundary-layer controlled absorption kinetics when their concentrations at pH 7.5 were 100-fold more dilute than the critical micelle concentrations (the CMC values being 9.5 $\times$ 10$\sp{-5}$ M for C$\sb{12}$ and 1.3 $\times$ 10$\sp{-5}$ M for C$\sb{14}$ in iso-osmotic pH 7.5 buffer solutions). The studies lead to the conclusion that only long chain fatty acid monomer species are taken up by the intestinal membrane. (Abstract shortened with permission of author.)