Glyceride-mimetic prodrugs incorporating self-immolative spacers promote lymphatic transport, avoid first-pass metabolism, and enhance oral bioavailability

Luojuan Hu, Tim Quach, Sifei Han, Shea F. Lim, Preeti Yadav, Danielle Senyschyn, Natalie L. Trevaskis, Jamie S. Simpson, Christopher J H Porter

Research output: Contribution to journalArticleResearchpeer-review

Abstract

First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self-immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.

Original languageEnglish
Pages (from-to)13700 –13705
Number of pages6
JournalAngewandte Chemie - International Edition
Volume55
Issue number44
DOIs
Publication statusPublished - 2016

Keywords

  • Drug delivery
  • Lymphatic transport
  • Metabolism
  • Prodrugs
  • Testosterone

Cite this

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title = "Glyceride-mimetic prodrugs incorporating self-immolative spacers promote lymphatic transport, avoid first-pass metabolism, and enhance oral bioavailability",
abstract = "First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self-immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.",
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Glyceride-mimetic prodrugs incorporating self-immolative spacers promote lymphatic transport, avoid first-pass metabolism, and enhance oral bioavailability. / Hu, Luojuan; Quach, Tim; Han, Sifei; Lim, Shea F.; Yadav, Preeti; Senyschyn, Danielle; Trevaskis, Natalie L.; Simpson, Jamie S.; Porter, Christopher J H.

In: Angewandte Chemie - International Edition, Vol. 55, No. 44, 2016, p. 13700 –13705.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lim, Shea F.

AU - Yadav, Preeti

AU - Senyschyn, Danielle

AU - Trevaskis, Natalie L.

AU - Simpson, Jamie S.

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