Han Sifei, Hu Luojuan, Quach Tim, Simpson Jamie S, Edwards Glenn A, Trevaskis Natalie L, Porter Christopher J H
School of Animal and Veterinary Sciences, Charles Sturt University , Boorooma Street, Wagga Wagga, New South Wales 2650, Australia.
Mol Pharm. 2016 Oct 3;13(10):3351-3361. doi: 10.1021/acs.molpharmaceut.6b00195. Epub 2016 Sep 21.
In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.
在先前的研究中，已表明模型免疫调节剂霉酚酸（MPA）的甘油三酯（TG）模拟前药可显著增强大鼠体内MPA相关物质的淋巴转运。然而，大鼠的胃肠道与狗和人类等高等物种的胃肠道有所不同，可能会低估淋巴转运。在此，已在清醒的灵缇犬中研究了前药策略的有效性，灵缇犬的胃肠道生理学更具人类代表性。对胸导管插管和完整（未插管）的灵缇犬口服给予母体药物（MPA）和前药（2-MPA-TG）后，检测了游离MPA和总MPA相关物质的生物利用度及淋巴转运情况。还测定了淋巴结和淋巴来源淋巴细胞中游离MPA的富集情况，以检查药物靶向淋巴内潜在作用位点的效率。通过生化整合到一系列位点特异性代谢过程中，与母体MPA相比，前药显著增加了（288倍）总MPA相关物质（以重新酯化的2-MPA-TG形式存在）的淋巴转运，并且与大鼠先前的数据（剂量的13.4%）相比，狗的淋巴转运程度显著更高（剂量的36.4%在淋巴中回收）。与给予母体药物的动物相比，2-MPA-TG衍生物在体内转化为母体MPA，导致淋巴结中MPA浓度显著增加（5-6倍），淋巴淋巴细胞中MPA浓度显著增加（21倍）。总之，数据表明MPA的TG前药有助于MPA在犬体内高效递送至淋巴系统，并表明TG前药策略在大型动物中可能比在大鼠中更有效地促进靶向递送。
