Intestinal Lymph Flow, and Lipid and Drug Transport Scale Allometrically From Pre-clinical Species to Humans.

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 <i>in vitro</i> studies and <i>in vivo</i> 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 = <i>a</i>M ^<i>E</i> where A is the lymph transport parameter, M is animal body mass, <i>a</i> is constant and <i>E</i> 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.