Supersaturation as a driving force for drug absorption from colloidal lipid species in the intestine

Abstract

This thesis seeks to elucidate the mechanism of drug absorption from the colloidal micellar and vesicular species that form in the gastrointestinal (GI) tract during lipid digestion. In addition to absorption from the free fraction of drug molecules that exist in equilibrium with drug solubilised in the colloidal reservoir, two alternative models of drug absorption were explored: (i) collisional drug absorption where lipid colloidal phases interact directly with the absorptive membrane, and (ii) supersaturation-enhanced absorption where transient changes to colloid structure and content in situ lead to drug supersaturation, thereby boosting drug thermodynamic activity and rendering solubilised drug more available for absorption via the free fraction. Collisional drug absorption was explored by comparing the intestinal absorptive flux of cinnarizine (CIN) from two distinctly different colloids (micelles vs. vesicles) that were matched for CIN solubilisation capacity and drug loading (and therefore thermodynamic activity). In these systems the number of micellar particles was substantially higher than that of vesicles, and as such collisional absorption of CIN was expected to be higher from micelles. The absorption of CIN from micelles and vesicles, however, was not statistically different, suggesting little collisional involvement in drug absorption. Receptor-mediated collisional absorption was examined by assessing CIN bioavailability from a lipid emulsion in the absence and presence of inhibitors of common lipid uptake transporters (e.g. SR-BI, CD36, NPC1L1). CIN bioavailability was unchanged by inhibitor co-administration. Collectively, the data suggest that collision-mediated uptake is not a significant driver for drug absorption from intestinal lipid colloidal phases, and that drug absorption occurs largely from the free fraction. Subsequently, attention turned to the possibility that drug supersaturation might be stimulated during endogenous processing of intestinal lipid colloidal phases. Two mechanisms were investigated: (i) interaction of lipid colloidal phases with bile secretions, where bile-induced changes to colloid microstructure may lead to reductions in drug solubilisation capacity and (ii) lipid absorption from intestinal colloids, where reductions in colloidal lipid content may reduce drug solubilisation capacity at the intestinal unstirred water layer (UWL). The addition of donor rat bile to CIN-loaded colloids (CIN was loaded at sub-saturated concentrations) resulted in a decrease in CIN solubilisation and the generation of CIN supersaturation. Bile-induced supersaturation was subsequently shown to increase the intestinal absorptive flux and systemic exposure of CIN from both medium-chain and long-chain lipid containing colloids. To assess the potential for lipid absorption to induce drug supersaturation, the intestinal absorptive flux of CIN from oleic acid-containing colloids was assessed under conditions of normal lipid absorption vs. inhibited lipid absorption (oleic acid absorption was inhibited by co-administration of amiloride, an inhibitor of UWL acidity). When oleic acid absorption was suppressed, the absorption of CIN was dramatically attenuated. Assessment of CIN solubilisation behaviour under conditions that simulate lipid absorption at the UWL subsequently indicated that supersaturation was likely to be responsible for the enhanced CIN absorption observed during normal lipid absorption. In summary, supersaturation appears to be an important driving force for drug absorption from lipid-based intestinal colloids. Two novel mechanisms have been identified by which drug supersaturation may be naturally triggered in the small intestine (bile dilution and lipid absorption). The findings enhance mechanistic understanding of the effects of lipids in food or formulations on drug absorption and are expected to inform the development of more rational design criteria for LBF.