The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

Abstract

The intestinal lymphatic system plays key roles in fluid transport, lipid absorption and immune function. Lymph flows directly from the small intestine via a series of lymphatic vessels and nodes that converge at the superior mesenteric lymph duct. Cannulation of the mesenteric lymph duct thus enables the collection of mesenteric lymph flowing from the intestine. Mesenteric lymph consists of a cellular fraction of immune cells (99% lymphocytes), aqueous fraction (fluid, peptides and proteins such as cytokines and gut hormones) and lipoprotein fraction (lipids, lipophilic molecules and apo-proteins). The mesenteric lymph duct cannulation model can therefore be used to measure the concentration and rate of transport of a range of factors from the intestine via the lymphatic system. Changes to these factors in response to different challenges (e.g., diets, antigens, drugs) and in disease (e.g., inflammatory bowel disease, HIV, diabetes) can also be determined. An area of expanding interest is the role of lymphatic transport in the absorption of orally administered lipophilic drugs and prodrugs that associate with intestinal lipid absorption pathways. Here we describe, in detail, a mesenteric lymph duct cannulated rat model which enables evaluation of the rate and extent of lipid and drug transport via the lymphatic system for several hours following intestinal delivery. The method is easily adaptable to the measurement of other parameters in lymph. We provide detailed descriptions of the difficulties that may be encountered when establishing this complex surgical method, as well as representative data from failed and successful experiments to provide instruction on how to confirm experimental success and interpret the data obtained. Video LinkThe video component of this article can be found at

Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative

“…The mesenteric lymph duct cannulation rat model is commonly used as to directly examine the transport of drugs after oral administration because it enables the collection of lymphatic fluids as it flows from the intestine [ 20 , 35 ]. The intestinal lymphatic transport of Dox after oral administration DoxQ and Dox was investigated in a mesenteric lymph duct cannulated model to assess whether the presence of quercetin facilitates lymphatic transport of Dox.…”

“…In contrast, highly lipophilic molecules and macromolecules such as proteins associate with chylomicrons in the intestinal mucosa and enter systemic circulation via the intestinal lymphatics pathway [ 19 ]. These lipophilic molecules and macromolecules are absorbed via lymphatic capillaries, which collect into the mesenteric lymph duct, followed by the thoracic lymph duct, and then drain into systemic circulation at the junction of the left subclavian and left jugular veins [ 19 , 20 ]. Therefore, molecules that are absorbed via the intestinal lymphatic pathway enter systemic circulation without passing through the liver.…”

“…Lipophilic drugs with LogP > 5 and solubility of >50 mg per g in long-chain triglyceride will likely have preferential absorption towards lymphatics owing to their ability to incorporate with intestinal lipoproteins [ 19 ]. If the drug of interest does not meet these criteria, it is also possible to alter the physicochemical properties of a small drug molecule by chemically modifying its lipophilicity, utilizing a lipid-based drug delivery system or designing a lipophilic prodrug where the parent drug is chemically conjugated to a lipophilic moiety via a linker that can be easily cleaved in vivo [ 19 , 20 , 21 , 22 ]. In this study, we utilized a novel Dox–quercetin conjugate where quercetin is designed to act as a lymphatically targeted carrier and may facilitate the intestinal transport of Dox into systemic circulation after oral administration and may also affect its disposition as well as overall systemic exposure after intravenous administration.…”

Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development

“…Based on reports examining fat absorption and entry into the lymph following ingestion of fats, it is apparent that there may be a lag time for the passage of fats into lymph and/or blood after ingestion of oral lipids. This is true in humans 16,17 , rats [18][19][20][21] and sheep 22 . In each case, there is evidence of a lag time (of up to 3 h) until lipid concentrations noticeably increase in lymph or plasma.…”

“…The role of fat absorption and transport is a major functional component of the lymphatic system. The lymphatic uptake of some drugs (which are lipophilic) is prone to be closely linked with the absorption of fats 20 . It is also not coincidental that many agents reportedly subject to lymphatic absorption [26][27][28][29][30] are also known to be highly bound to plasma proteins, including lipoproteins [31][32][33][34][35] .…”