Han Sifei, Hu Luojuan, Quach Tim, Simpson Jamie S, Trevaskis Natalie L, Porter Christopher J H
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
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.
J Pharm Sci. 2016 Feb;105(2):786-796. doi: 10.1002/jps.24670. Epub 2016 Jan 29.
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.
甘油三酯（TG）模拟前药（1,3-二棕榈酰-2-霉酚酰甘油，2-MPA-TG）在生物化学上整合到肠道脂质转运和脂蛋白组装途径中，从而促进霉酚酸（MPA）向淋巴系统的递送。由于脂蛋白（LP）的形成即使在禁食状态下也会持续发生，因此本研究旨在确定2-MPA-TG的淋巴转运是否依赖于共同给药的外源性脂质。前药与大鼠消化液的体外孵育和原位肠道灌注实验表明，前药的水解和吸收相对不受制剂中脂质含量的影响。然而，在大鼠体内的研究表明，给予较高量脂质后，TG和2-MPA-TG的淋巴转运显著更高，并且油酸（C18:1）在促进前药转运方面比具有更高不饱和度的脂质更有效。2-MPA-TG和TG在淋巴中的回收率密切相关（R(2) = 0.99），超过97%的前药与乳糜微粒相关。普朗尼克L81对LP组装的抑制同时抑制了2-MPA-TG和TG的淋巴转运。总之，尽管TG模拟前药有效地整合到TG再合成途径中，但仍需要共同给予脂质以支持有效的淋巴转运。
