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Exploring the Impact of Drug Properties on the Extent of Intestinal Lymphatic Transport - In Vitro and In Vivo Studies

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Abstract

Purpose

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.

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Abbreviations

BSA:

Bovine serum albumin

DDT:

Dichlorodiphenyltrichloroethane

FA:

Fatty acids

FaSSIF:

Fasted simulated state intestinal fluid

HPLC:

High performance liquid chromatography

LCFA:

Long chain fatty acids

LCT:

Long chain triglyceride

LOQ:

Limit of quantitation

PBS:

Phosphate buffered saline

P-gp:

P-glycoprotein

TG:

Triglyceride

TLC:

Thin layer chromatography

TRL:

Triglyceride rich lipoproteins

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Authors and Affiliations

  1. School of Pharmacy, Trinity College Dublin, Dublin 2, Ireland

    Emma Lawless

  2. Pharmacodelivery Group, School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland

    Brendan T. Griffin, Aoife O’Mahony & Caitriona M. O’Driscoll

Authors
  1. Emma Lawless
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  2. Brendan T. Griffin
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  3. Aoife O’Mahony
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  4. Caitriona M. O’Driscoll
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Corresponding author

Correspondence to Caitriona M. O’Driscoll.

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Lawless, E., Griffin, B.T., O’Mahony, A. et al. Exploring the Impact of Drug Properties on the Extent of Intestinal Lymphatic Transport - In Vitro and In Vivo Studies. Pharm Res 32, 1817–1829 (2015). https://doi.org/10.1007/s11095-014-1578-x

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  • DOI: https://doi.org/10.1007/s11095-014-1578-x

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