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 an d lipophilic drugs can gain access to the systemic circulation. Compou nds absorbed by the intestinal lymphatics drain via the thoracic lymph and enter the systemic circulation at the junction of the left intern al jugular vein and the left subclavian vein, thereby avoiding potenti al first pass metabolism. Consequently, drug transport via the intesti nal lymphatics may confer delivery advantages in terms of increased bi oavailability (via a reduction in presystemic metabolism) and the poss ibility of directing delivery to the lymphatic system. The digestion a nd absorption of lipids is central to the lymphatic transport of lipop hilic 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 last ly, 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 formu lation optimisation. The physico-chemical and metabolic features of pr odrugs designed for enhanced lymphatic transport are discussed, and th e advantages and disadvantages of various promoiety strategies are bri efly described. Common formulation approaches designed to enhance lymp hatic drug delivery are reviewed, with discussion of some recent examp les. Finally, the requirement for exogenous lipid to facilitate lympha tic drug transport, and the possibility of directing 'moderately' lipo philic compounds through the lymph via formulation approaches, are add ressed.