Trevaskis Natalie L, Lee Given, Escott Alistair, Phang Kian Liun, Hong Jiwon, Cao Enyuan, Katneni Kasiram, Charman Susan A, Han Sifei, Charman William N, Phillips Anthony R J, Windsor John A, Porter Christopher J H
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
Front Physiol. 2020 May 21;11:458. doi: 10.3389/fphys.2020.00458. eCollection 2020.
The intestinal lymphatic system transports fluid, immune cells, dietary lipids, and highly lipophilic drugs from the intestine to the systemic circulation. These transport functions are important to health and when dysregulated contribute to pathology. This has generated significant interest in approaches to deliver drugs to the lymphatics. Most of the current understanding of intestinal lymph flow, and lymphatic lipid and drug transport rates, comes from studies and animal studies. In contrast, intestinal lymphatic transport studies in human subjects have been limited. Recently, three surgical patients had cannulation of the thoracic lymph duct for collection of lymph before and during a stepwise increase in enteral feed rate. We compared these data to studies where we previously enterally administered controlled quantities of lipid and the lipophilic drug halofantrine to mice, rats and dogs and collected lymph and blood (plasma). The collected lymph was analyzed to compare lymph flow rate, triglyceride (TG) and drug transport rates, and plasma was analyzed for drug concentrations, as a function of enteral lipid dose across species. Lymph flow rate, TG and drug transport increased with lipid administration in all species tested, and scaled allometrically according to the equation A = M where A is the lymph transport parameter, M is animal body mass, is constant and is the allometric exponent. For lymph flow rate and TG transport, the allometric exponents were 0.84-0.94 and 0.80-0.96, respectively. Accordingly, weight normalized lymph flow and TG mass transport were generally lower in larger compared to smaller species. In comparison, mass transport of drug via lymph increased in a greater than proportional manner with species body mass with an exponent of ∼1.3. The supra-proportional increase in lymphatic drug transport with species body mass appeared to be due to increased partitioning of drug into lymph rather than blood following absorption. Overall, this study proposes that intestinal lymphatic flow, and lymphatic lipid and drug transport in humans is most similar to species with higher body mass such as dogs and underestimated by studies in rodents. Notably, lymph flow and lipid transport in humans can be predicted from animal data via allometric scaling suggesting the potential for similar relationships with drug transport.
肠道淋巴系统将液体、免疫细胞、膳食脂质和高度亲脂性药物从肠道转运至体循环。这些转运功能对健康至关重要，一旦失调则会引发病变。这激发了人们对将药物输送至淋巴管方法的浓厚兴趣。目前，关于肠道淋巴流动以及淋巴脂质和药物转运速率的大部分认识都来自于研究和动物研究。相比之下，人体肠道淋巴转运研究一直较为有限。最近，三名外科手术患者在逐步增加肠内喂养速率之前和期间，通过插管胸导管来收集淋巴液。我们将这些数据与之前对小鼠、大鼠和狗进行的研究数据进行了比较，在那些研究中，我们向它们肠内给予了定量的脂质和亲脂性药物卤泛群，并收集了淋巴液和血液（血浆）。对收集到的淋巴液进行分析，以比较淋巴流速、甘油三酯（TG）和药物转运速率，对血浆进行分析以检测药物浓度，这些都是跨物种肠内脂质剂量的函数。在所有测试物种中，淋巴流速、TG和药物转运随着脂质给药而增加，并根据公式A = M 进行异速生长缩放，其中A是淋巴转运参数，M是动物体重， 是常数， 是异速生长指数。对于淋巴流速和TG转运，异速生长指数分别为0.84 - 0.94和0.80 - 0.96。因此，与较小物种相比，较大物种的体重标准化淋巴流速和TG质量转运通常较低。相比之下，药物通过淋巴的质量转运随着物种体重以大于比例的方式增加，指数约为1.3。随着物种体重增加，淋巴药物转运超比例增加似乎是由于药物吸收后在淋巴而非血液中的分配增加所致。总体而言，本研究表明人体肠道淋巴流动以及淋巴脂质和药物转运与体重较高的物种（如狗）最为相似，而啮齿动物研究对其有所低估。值得注意的是，人体淋巴流动和脂质转运可通过异速生长缩放从动物数据中预测出来，这表明与药物转运可能存在类似关系。
