title: Constitutive Triglyceride Turnover into the Mesenteric Lymph Is Unable to Support Efficient Lymphatic Transport of a Biomimetic Triglyceride Prodrug.
abstract: The triglyceride (TG) mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) biochemically integrates into intestinal lipid transport and lipoprotein assembly pathways and thereby promotes the delivery of mycophenolic acid (MPA) into the lymphatic system. As lipoprotein (LP) formation occurs constitutively, even in the fasted state, the current study aimed to determine whether lymphatic transport of 2-MPA-TG was dependent on coadministered exogenous lipid. In vitro incubation of the prodrug with rat digestive fluid and in situ intestinal perfusion experiments revealed that hydrolysis and absorption of the prodrug were relatively unaffected by the quantity of lipid in formulations. In vivo studies in rats, however, showed that the lymphatic transport of TG and 2-MPA-TG was significantly higher following administration with higher quantities of lipid and that oleic acid (C18:1) was more effective in promoting prodrug transport than lipids with higher degrees of unsaturation. The recovery of 2-MPA-TG and TG in lymph correlated strongly (R(2) = 0.99) and more than 97% of the prodrug was associated with chylomicrons. Inhibition of LP assembly by Pluronic L81 simultaneously inhibited the lymphatic transport of 2-MPA-TG and TG. In conclusion, although the TG mimetic prodrug effectively incorporates into TG resynthetic pathways, lipid coadministration is still required to support efficient lymphatic transport.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Sifei
authors.initials: S
authors.lastname: Han
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Luojuan
authors.initials: L
authors.lastname: Hu
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Quach
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Simpson
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: natalie.trevaskis@monash.edu.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Trevaskis
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: chris.porter@monash.edu.
authors.forename: Christopher J H
authors.initials: CJH
authors.lastname: Porter
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008196:Lymph / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D014280:Triglycerides / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D011355:Prodrugs; D014280:Triglycerides
keywords: intestinal absorption; lipids/lipoproteins; lymphatic transport; prodrugs; site-specific delivery