Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport, Avoid First‐Pass Metabolism, and Enhance Oral Bioavailability. Issue 44 (2nd August 2016)

• Record Type: Journal Article
• Authors: Hu, Luojuan; Quach, Tim; Han, Sifei; Lim, Shea F.; Yadav, Preeti; Senyschyn, Danielle; Trevaskis, Natalie L.; Simpson, Jamie S.; Porter, Christopher J. H.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 44(2016)
• Page Start: 13700
• Page End: 13705
• Publication Date: 2016-08-02
• Subjects: drug delivery -- lymphatic transport -- metabolism -- prodrugs -- testosterone; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201604207
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Bioavailable lymphotropic prodrugs : The oral bioavailability of testosterone is significantly enhanced by the generation of glyceride‐based prodrugs characterized by self‐immolative triggers to promote drug release. The prodrugs redirect drug absorption away from the portal blood and the liver, and instead promote drug delivery directly to the general circulation through the lymphatic system.