Peer-Reviewed Journal Details
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Lawless, E.,Griffin, B. T.,O'Mahony, A.,O'Driscoll, C. M.
2015
May
Pharmaceutical Researchpharmaceutical Research
Exploring the Impact of Drug Properties on the Extent of Intestinal Lymphatic Transport - In Vitro and In Vivo Studies
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32
55
1817
1829
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. 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. 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. 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.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. 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. 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. 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.
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://WOS:000352225300023://WOS:000352225300023
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