Intestinal lymphatic transport for drug delivery

Abstract

Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically-active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model (in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug-based drug delivery systems for enhancing lymphatic drug transport.

Fig. 1

Drug absorption via the intestinal lymphatic system and portal vein. FA = fatty acid, MG = monoglyceride, TG = triglyceride, LP = lipoprotein.

Fig. 2

Schematic diagram describing the sequential steps in the digestion of lipids and absorption via de portal blood and intestinal lymphatics.

Fig. 3

Cumulative lymphatic transport of halofantrine (Hf) (percentage of administered dose, mean ± SE) in thoracic lymph duct-cannulated dogs after fasted administration (open symbols, n = 3) or post-prandial administration (closed symbols, n = 4) of 100 mg halofantrine (free base).

Fig. 4

Schematic representation of the double jeopardy theory. Substrates are represented by triangles whereas products of enzymes or metabolites are represented by pentagons.

Fig. 5

Types of lipidic carriers: fatty acids, glycerides and phospholipids. In the case of fatty acids, the drug is attached directly to the carboxylate or to a modified ω-atom. Drug-glycerides conjugates are represented here by a 1,3-diglyceride where the drug is in position-2. Phospholipid prodrugs consist either in drugs linked to the phosphate group or to the glycerol backbone, in this case, the drug replaces a fatty acid.