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DOI: 10.1007/s11095-013-1000-0Pages: 3254-3270

A Mouse Model to Evaluate the Impact of Species, Sex, and Lipid Load on Lymphatic Drug Transport

1. Monash University (Parkville Campus), Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences

2. University of Cincinnati, Department of Pathology, Genome Research Institute

Correspondence to:
Christopher J. H. Porter
Tel: +61-3-99039649
Fax: +61-3-99039853
Email: Chris.Porter@monash.edu

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Abstract

Purpose

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 14C-lipid doses. For bioavailability calculation, animals were intravenuosly administered halofantrine. Lymph or blood samples were taken and halofantrine, triglyceride, phospholipid and 14C-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.

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  • Accepted: Jan 28, 2013
  • Online: Feb 21, 2013

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