Lipophilic prodrugs designed for intestinal lymphatic transport

The intestinal lymphatics are a specialised absorption and transport pathway for highly lipophilic drugs, lipids and lipidic derivatives, and lipophilic xenobiotics. Once a drug has gained access to the intestinal lymphatics (generally in association with specific lipoproteins formed by the enterocyte in response to co-administered lipid), it drains through the mesenteric lymphatics gaining access to the systemic circulation at the junction of the left internal jugular and left subclavian veins. Therefore, the major drug delivery opportunities associated with intestinal lymphatic transport of lipophilic prodrugs are the potential for (i) by-passing hepatic first pass metabolism after oral dosing, and (ii) targeting drugs to regions of the lymphatics. This review describes the necessary physicochemical and metabolic features of prodrugs designed for enhanced intestinal lymphatic transport. For lymphatic transport to be quantitatively important after oral administration, simple ester/ether approaches generally do not lead to significant lymphatic transport of the administered prodrug. Application of monoglyceride or triglyceride mimics, and more recently phospholipid mimics, appear to hold promise for selective lymphatic delivery. Examples of lipophilic prodrugs designed to avoid pre-systemic clearance, reduce gastrointestinal intolerance, and for targeting various disease states resident within the intestinal lymphatics are presented.