Exploring the impact of drug properties on the extent of intestinal lymphatic transport - in vitro and in vivo studies.

PURPOSE: Intestinal lymphatic transport of specific lipophilic drugs offers therapeutic advantages and maximises oral bioavailability. The aims of this study were; to compare intestinal lymphatic transport of a range of drugs and to investigate the influence of cyclosporine A on the mechanism/extent of lymphatic transport. METHODS: Caco2 cells and an anaesthetised mesenteric lymphatic cannulated rat model were used for in vitro and in vivo studies. Lymphatic transport of three lipophilic drugs was directly compared in a long chain fatty acid formulation. In addition, the impact of cyclosporine A on triglyceride turnover was evaluated in vivo and in vitro. RESULTS: The extent of intestinal lymphatic transport in rats was positively correlated with drug solubility in triglyceride and negatively correlated with drug aqueous solubility. Cyclosporine A displayed non-linear lymphatic transport kinetics and reduced intestinal lymph triglyceride. In vitro experiments indicated that the cellular processes affected were intracellular lipid processing and/or lipid secretion. CONCLUSIONS: The linear correlations obtained using a range of lipophilic drugs confirm that the simplified approach of determining aqueous or triglyceride drug solubility is useful in predicting the extent of lymphatic transport. In vitro experiments correlated with in vivo observations, demonstrating the usefulness of the Caco-2 model for mechanistic investigations.

Stimulation of triglyceride-rich lipoprotein secretion by polysorbate 80: in vitro and in vivo correlation using Caco-2 cells and a cannulated rat intestinal lymphatic model.

PURPOSE: To assess the effects of polysorbates 80 and 60 on intestinal lipoprotein processing in vitro, using Caco-2 cells, and to compare the results with those obtained using an in vivo intestinal lymphatic cannulated rat model. METHODS: Caco-2 monolayers were used to monitor changes in lipoprotein secretion following exposure to excipients. In vivo data was obtained by monitoring intestinal lymphatic triglyceride levels following intraduodenal administration of the excipient to an anesthetised mesenteric lymph cannulated rat. RESULTS: Caco-2 cells digested the polysorbate 80 to liberate oleic acid, which was used by the cells to enhance basolateral secretion of triglyceride-rich lipoproteins including chylomicrons. This response was not seen with polysorbate 60. Polysorbate 80 elicited a similar response in vivo in the rat model, stimulating enhanced triglyceride secretion in mesenteric lymph. Inhibition of lipoprotein secretion by Cremophor EL in Caco-2 cells was reversed by co-administration with polysorbate 80. CONCLUSIONS: Polysorbate 80 promoted chylomicron secretion in Caco-2 cells and counteracted the inhibitory effects of other surfactants. These properties, in tandem with its P-gp inhibitory activity, make polysorbate 80 an ideal excipient for lymphotrophic vehicles. The ability to predict the in vivo response to Polysorbate 80 implies that the Caco-2 model is useful for studying absorption mechanisms from oral lipid-based formulations.