title: Exploring the impact of drug properties on the extent of intestinal lymphatic transport - in vitro and in vivo studies.
abstract: OBJECTIVE
  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.
authors.affiliation: School of Pharmacy, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Emma
authors.initials: E
authors.lastname: Lawless
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.forename: Aoife
authors.initials: A
authors.lastname: O'Mahony
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D003634:DDT / Q000737:chemistry / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008196:Lymph / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D019258:Saquinavir / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D014280:Triglycerides / Q000378:metabolism
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D014280:Triglycerides; D016572:Cyclosporine; D003634:DDT; D019258:Saquinavir