Pharmaceutical Research

, Volume 30, Issue 12, pp 3254–3270 | Cite as

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

  • Natalie L. Trevaskis
  • Suzanne M. Caliph
  • Gary Nguyen
  • Patrick Tso
  • William N. Charman
  • Christopher J. H. Porter
Research Paper
First Online:
Received:
Accepted:

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.

KEY WORDS

lipid lymphatic drug transport mouse sex species 

ABBREVIATIONS

AUC

Area under the plasma concentration-time curve

FA

Fatty acid

Hf

Halofantrine

HPLC

High Performance Liquid Chromatography

LC-MS

HPLC-mass spectrometry

PL

Phospholipid

SEDDS

Self-Emulsifying Drug Delivery System

TG

Triglyceride

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Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Luojuan Hu for her technical assistance in the mouse bioavailability experiments and Dr Juergen Bulitta for assistance in calculating bioavailability in the mice.

Supplementary material

11095_2013_1000_MOESM1_ESM.doc (91 kb)
Supplementary figure 1 Panel A: Cumulative% of the dose of halofantrine (Hf), and Panel B: Cumulative triglyceride (TG, mg) mass, transported in the mesenteric lymph following administration of 1.6 mg/kg halofantrine and 18.1 mg/kg long chain lipid, as an oleic acid emulsion administered into the intestine of anaesthetised rats (●) or as a pre-dispersed self-emulsifying drug delivery system via oral administration to conscious rats (○). Data represent mean ± SEM for n = 3–4 animals. (DOC 91 kb)
11095_2013_1000_MOESM2_ESM.doc (93 kb)
Supplementary figure 2 Panel A. Mass of total, endogenous and exogenous fatty acid transported into the lymph of male (black bars) or female (white bars) rats, and Panel B. Cumulative% of the dose of halofantrine transported in the lymph of male (●) or female (○) rats, over 8 h following intraduodenal administration of 1.6 mg/kg halofantrine in an emulsion containing 18.1 mg/kg long chain lipid. Data represent mean ± SEM for n = 3–4 animals. *Parameter significantly greater in male when compared to female animals (α < 0.05). (DOC 93 kb)
11095_2013_1000_MOESM3_ESM.doc (101 kb)
Supplementary figure 3 Plasma halofantrine (Hf) concentration vs time profiles in mice (Panel A) and rats (Panel B) following administration of 1.6 mg/kg halofantrine and 18.1 mg/kg long chain lipid as an oleic acid emulsion administered into the intestine of anaesthetised animals (●) or as a pre-dispersed self-emulsifying drug delivery system via oral administration to conscious animals (○). Data represent mean ± SEM for n = 3–6 animals. (DOC 101 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Natalie L. Trevaskis
    • 1
  • Suzanne M. Caliph
    • 1
  • Gary Nguyen
    • 1
  • Patrick Tso
    • 2
  • William N. Charman
    • 1
  • Christopher J. H. Porter
    • 1
  1. 1.Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical SciencesMonash University (Parkville Campus)ParkvilleAustralia
  2. 2.Department of Pathology, Genome Research InstituteUniversity of CincinnatiCincinnatiUSA

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