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Profiling the Role of Deacylation-Reacylation in the Lymphatic Transport of a Triglyceride-Mimetic Prodrug

Pharmaceutical Research volume 32, pages 1830–1844 (2015)Cite this article

ABSTRACT

Purpose

Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs.

Methods

In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments were conducted in the presence and absence of orlistat and A922500 (inhibitors of lipolysis and TG re-esterification, respectively), to evaluate the importance of 2-MPA-TG digestion and re-esterification of 2-MPA-MG (the 2-monoglyceride derivative) in promoting lymphatic transport.

Results

2-MPA-TG was rapidly hydrolysed to 2-MPA-MG on incubation with fresh bile and pancreatic fluid (BPF), but not in simulated gastric fluid, heat-inactivated BPF or BPF + orlistat. Orlistat markedly decreased lymphatic transport and systemic exposure of 2-MPA-TG derivatives suggesting that inhibition of pancreatic lipase hindered luminal digestion and absorption of the prodrug. A922500 also significantly decreased lymphatic transport of 2-MPA-TG but redirected MPA to the portal blood, suggesting that hindered re-acylation of 2-MPA-MG resulted in intracellular degradation.

Conclusion

Incorporation into TG deacylation-reacylation pathways is a critical determinant of the utility of lymph directed TG-mimetic prodrugs.

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Abbreviations

BPF:

Bile and pancreatic fluid

DG:

Diglyceride

DGAT:

Diacylglycerol acyltransferease

DGTA:

Diacylglycerol transacylase

FA:

Fatty acid

ID:

Intraduodenal

MG:

Monoglyceride

MGAT:

Monoacylglycerol acyltransferase

MPA:

Mycophenolic acid

MW:

Molecular weight

SGF:

Simulated gastric fluid

TG:

Triglyceride

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ACKNOWLEDGMENTS AND DICLOSURES

This work was financially supported by the National Health and Medical Research Council of Australia and the Australian Research Council. The authors thank Dr. David Shackleford for assistance in PK analysis and Ms Gracia for technical assistance during sample collection and analysis.

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Authors and Affiliations

  1. Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, 3052, Australia

    Sifei Han, Luojuan Hu, Natalie L. Trevaskis & Christopher J. H. Porter

  2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, 3052, Australia

    Tim Quach & Jamie S. Simpson

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  1. Sifei Han
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  2. Luojuan Hu
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Correspondence to Natalie L. Trevaskis or Christopher J. H. Porter.

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Han, S., Hu, L., Quach, T. et al. Profiling the Role of Deacylation-Reacylation in the Lymphatic Transport of a Triglyceride-Mimetic Prodrug. Pharm Res 32, 1830–1844 (2015). https://doi.org/10.1007/s11095-014-1579-9

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KEY WORDS

  • DGAT
  • lipase
  • lymphatic transport
  • prodrug
  • triglyceride mimetic