Lipophilic drugs lymphatic transport

In addition to increased overall bioavailability of lipophilic molecules, lymphatic transport of a drug provides further advantages, including avoidance of hepatic first pass metabolism, a potential to target specific disease states known to spread via the lymphatics, and improved plasma profile of the drug. 

Charman WN and Stella VJ (1986) Estimating the Maximal Potential for Intestinal Lymphatic Transport of Lipophilic Drug Molecules. Int J Pharm 34 pp 175-178. 

Bioavailability of lipophilic drugs may be enhanced also by the stimulation of the intestinal lymphatic transport pathway. This issue will be addressed separately (Section 6.3.2.1). 

FIGURE 6.5 Relationship between the extent of intestinal lymphatic transport of a drug and lipophilicity after oral administration. (From Stella, VJ. and Pochopin, N.L. Lymphatic Transport of Drugs, Charman, W.N. and Stella, V.J., Eds., CRC Press, Boca Raton, 1992, p. 181. With permission.)... 

Following oral administration of a lipophilic drug, the main route for the drug to access into the intestinal lymphatics is transcellular, by tracking the same pathway as the lipidic nutrients in food, which use the physiological intestinal lipid transport system. Hence, a brief description of this process is described. 

Charman, W.N., and V.J. Stella. 1986. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int J Pharm 34 175. 

Stella, V.J., and N.L. Pochopin. 1992. Lipophilic prodrugs and the promotion of intestinal lymphatic drug transport. In Lymphatic transport of drugs, eds. W.N. Charman, and Y J. Stella, 181. Boca Raton CRC Press. 

Dahan, A., and A. Hoffman. 2005. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur J Pharm Sci 24 381. 

After absorption, most drugs and xenobiotics traverse the enterocyte and are absorbed into the portal blood. A small number of highly lipophilic drugs, however, are transported to the systemic circulation by means of the intestinal lymphatics. 

The consequences of intestinal lymphatic transport are therefore more wide ranging than the opportunity to target the intestinal and central lymph and to avoid first-pass metabolism. Indeed, drug transport by means of the intestinal lymph may markedly alter the patterns of subsequent systemic drug clearance and disposition, and these profound alterations could be stimulated simply by a change in formulation. Importantly, the common approach of the use of plasma AUC as an indicator of the available fraction may be misplaced when dealing with lipophilic and lymphotropic drug molecules. 

D. J. Hauss, S. Mehta, G. W. Radebaugh, Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid-regulator drug, via a formulation approach, hit. J. Pharmaceut. 108 85-93 (1994). 

R. Myers and V. J. Stella, Factors affecting the lymphatic transport of penclomedine (NSC-338720), a lipophilic cytotoxic drug comparison to DDT and hexachloro-benzene. Int. J. Pharm. 80 51-62 (1992). 

The portal blood represents the major pathway for the majority of orally administered drugs as it has higher capacity to transport both water soluble and poorly water soluble compounds. During this process, hydrophilic molecules are carried to the liver via the hepatic portal vein, and then by the hepatic artery gain across to the systemic circulation for subsequent delivery to their sites of action. On the other hand, highly lipophilic drugs (log P > 5) that cross the same epithelial barrier are transported to the intestinal lymphatics, which directly delivers them to the vena cava, thereby bypassing the hepatic first-pass metabolism. ... 

Sterile parenteral oil-in-water emulsions have been used extensively for over 40 years for the intravenous administration of fats, carbohydrates, and vitamins to debilitated patients. Several vegetable oil-in-water emulsions are now available commercially with droplet sizes similar to that of chylomicrons (approximately 0.5-2 pm), the natural fat droplets in the blood that transport ingested fats to the lymphatic and circulatory systems (Table 1). More recently, such emulsions have been employed as intravenous carriers for poorly water-soluble lipophilic drugs such as vitamin K (e.g.. Sterile Phytonadione Injection U.S.P.) diazepam... 

---