Abstract
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 in vitro studies and in vivo 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 = aME where A is the lymph transport parameter, M is animal body mass, a is constant and E 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.
Highlights
Following ingestion, dietary lipids, lipid soluble vitamins, and highly lipophilic drugs are assembled into triglyceride-rich lipoproteins in the enterocytes and transported from the intestine to the systemic circulation via the lymphatic system (Dixon, 2010; Trevaskis et al, 2015; Bernier-Latmani and Petrova, 2017; Cifarelli and Eichmann, 2019)
We found that lymph TG transport generally increases with enteral lipid administration, as would be expected since in the small intestine most lipids are assembled into TG-rich lipoproteins that are transported via the intestinal lymphatics (Kassis et al, 2012; Trevaskis et al, 2015)
Intestinal lymph flow and lipid transport scale allometrically with an exponent of 0.8–0.96 and weight-normalized intestinal lymph flow and lipid transport decreases with increasing species size
Summary
Dietary lipids, lipid soluble vitamins, and highly lipophilic drugs are assembled into triglyceride-rich lipoproteins in the enterocytes and transported from the intestine to the systemic circulation via the lymphatic system (Dixon, 2010; Trevaskis et al, 2015; Bernier-Latmani and Petrova, 2017; Cifarelli and Eichmann, 2019). The functions of the lymphatic system are important to health and when dysregulated can contribute to a range of pathologies including obesity, cardiovascular diseases, inflammatory diseases, acute and critical illnesses, and cancers (Alitalo, 2011; Trevaskis et al, 2015; Petrova and Koh, 2018). Knowledge of thoracic lymph flow and composition in human patients has largely come from these studies (Blomstrand and Dahlback, 1960; Schlierf et al, 1969; Wang et al, 2016). This compares to recovery of 2.8–3.3 and 1.9% of the dose of testosterone undecanoate in lymph after administration to greyhound dogs and rats in similar commercial formulations (Shackleford et al, 2003; Hu et al, 2016)
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