Uptake of drugs into the intestinal lymphatics after oral administration

The intestinal lymphatics are a specialised absorption pathway through which dietary lipids, fat soluble vitamins, lipophilic xenobiotics and lipophilic drugs can gain access to the systemic circulation. Compounds absorbed by the intestinal lymphatics drain via the thoracic lymph and enter the systemic circulation at the junction of the left internal jugular vein and the left subclavian vein, thereby avoiding potential first pass metabolism. Consequently, drug transport via the intestinal lymphatics may confer delivery advantages in terms of increased bioavailability (via a reduction in presystemic metabolism) and the possibility of directing delivery to the lymphatic system. The digestion and absorption of lipids is central to the lymphatic transport of lipophilic drugs, and the relevant aspects of these processes are described in the first section of this review. Secondly, methods for predicting and assessing lymphatic drug transport are briefly reviewed, and lastly, common approaches for promoting lymphatic transport are addressed. In this review, the promotion of intestinal lymphatic drug transport is addressed from two standpoints, namely, prodrug formation and formulation optimisation. The physico-chemical and metabolic features of prodrugs designed for enhanced lymphatic transport are discussed, and the advantages and disadvantages of various promoiety strategies are briefly described. Common formulation approaches designed to enhance lymphatic drug delivery are reviewed, with discussion of some recent examples. Finally, the requirement for exogenous lipid to facilitate lymphatic drug transport, and the possibility of directing 'moderately' lipophilic compounds through the lymph via formulation approaches, are addressed.