Glyceride-Mimetic Prodrugs Incorporating Self-Immolative Spacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability
| Autor: | Danielle Senyschyn, Christopher J.H. Porter, Natalie L. Trevaskis, Tim Quach, Jamie S. Simpson, Shea Fern Lim, Luojuan Hu, Preeti Yadav, Sifei Han |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Administration Oral Biological Availability 02 engineering and technology Pharmacology 01 natural sciences Catalysis Glycerides Lymphatic System 03 medical and health sciences First pass effect Animals Humans Prodrugs media_common 010405 organic chemistry Chemistry General Medicine General Chemistry Prodrug 021001 nanoscience & nanotechnology 0104 chemical sciences Bioavailability 030104 developmental biology Lymphatic system Targeted drug delivery Drug delivery 0210 nano-technology Drug metabolism |
| Zdroj: | Angewandte Chemie (International ed. in English). 55(44) |
| ISSN: | 1521-3773 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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