title: A mouse model to evaluate the impact of species, sex, and lipid load on lymphatic drug transport.
abstract: OBJECTIVE
  To establish a lymph-cannulated mouse model, and use the model to investigate the impact of lipid dose on exogenous and endogenous lipid recruitment, and drug transport, into the lymph of males versus females. Finally, lymphatic transport and drug absorption in the mouse were compared to other pre-clinical models (rats/dogs).
  
  
  METHODS
  Animals were orally or intraduodenally administered 1.6 mg/kg halofantrine in low or high (14)C-lipid doses. For bioavailability calculation, animals were intravenuosly administered halofantrine. Lymph or blood samples were taken and halofantrine, triglyceride, phospholipid and (14)C-lipid concentrations measured.
  
  
  RESULTS
  Lymphatic lipid transport increased linearly with lipid dose, was similar across species and in male/female animals. In contrast, lymphatic transport of halofantrine differed markedly across species (dogs>rats>mice) and plateaued at higher lipid doses. Lower bioavailability appeared responsible for some species differences in halofantrine lymphatic transport; however other systematic differences were involved.
  
  
  CONCLUSIONS
  A contemporary lymph-cannulated mouse model was established which will enable investigation of lymphatic transport in transgenic and disease models. The current study found halofantrine absorption and lymphatic transport are reduced in small animals. Future analyses will investigate mechanisms involved, and if similar trends occur for other drugs, to establish the most relevant model(s) to predict lymphatic transport in humans.
authors: Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria, Australia, 3052, Natalie.Trevaskis@monash.edu.
authors: Natalie L
authors: NL
authors: Trevaskis
authors: Suzanne M
authors: SM
authors: Caliph
authors: Gary
authors: G
authors: Nguyen
authors: Patrick
authors: P
authors: Tso
authors: William N
authors: WN
authors: Charman
authors: Christopher J H
authors: CJ
authors: Porter
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D005260:Female; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D014677:Pharmaceutical Vehicles / Q000378:metabolism*; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D010743:Phospholipids / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013045:Species Specificity; D014280:Triglycerides / Q000097:blood
chemical_list: D000962:Antimalarials; D008055:Lipids; D014677:Pharmaceutical Vehicles; D010616:Phenanthrenes; D010743:Phospholipids; D014280:Triglycerides; C023768:halofantrine