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.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Luojuan
authors.initials: L
authors.lastname: Hu
authors.affiliation: Medicinal Chemistry, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Quach
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Sifei
authors.initials: S
authors.lastname: Han
authors.affiliation: Medicinal Chemistry, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Shea F
authors.initials: SF
authors.lastname: Lim
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Preeti
authors.initials: P
authors.lastname: Yadav
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Senyschyn
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Natalie L
authors.identifier: 0000-0001-9538-549X
authors.initials: NL
authors.lastname: Trevaskis
authors.affiliation: Medicinal Chemistry, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. jamie.simpson@monash.edu.
authors.forename: Jamie S
authors.identifier: 0000-0002-8894-422X
authors.initials: JS
authors.lastname: Simpson
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. chris.porter@monash.edu.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. chris.porter@monash.edu.
authors.forename: Christopher J H
authors.identifier: 0000-0003-3474-7551
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D005989:Glycerides / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008208:Lymphatic System / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D005989:Glycerides; D011355:Prodrugs
keywords: drug delivery; lymphatic transport; metabolism; prodrugs; testosterone