The lymphatic route has been suggested as a method of by-passing first-pass metabolism for extremely lipid soluble drugs. It has been argued that lipophilic drugs may become incorporated into lipid micelles and transformed into chylomicrons by the epithelium before being released into the lymphatic circulation. All the lymph from the lower part of the body flows up through the thoracic duct and empties into the venous system of the left internal jugular vein, thus avoiding the hepatic portal system. In order to be transported in the chylomicrons, the drug must be extremely lipophilic. The ratio of portal blood flow to intestinal lymph flow in the rat is approximately 500:1. Although lymph is the major transport route for fats, it only contains 1% lipids. The overall effect is to make systemic absorption 50,000 times more efficient than lymphatic absorption. In order for a drug to be transported at equal rates by both lymphatic and systemic circulations, the drug must be 50,000 times more soluble in the chylomicrons than the plasma, i.e have a partition coefficient of 50,000 (log P=4.7)94.
As expected, in practice the lymphatic route is of little importance, except for those materials which are extremely lipophilic, for example insecticides such as dichlorodiphenyltrichloroethane (DDT), in which the loading of drug in the chylomicrons is as high as 0.6 to 2% by weight95 96. These values are approximately 6 to 20% of the saturated solubility of DDT in triglycerides.
Studies of mesenteric lymph and blood plasma levels of p-amino salicylic acid delivered intra-duodenally to rats suggested that the drug was directly transported to the lymphatics97. In addition, tetracycline was found in the central lacteal of the villi after administration, but this route was insignificant compared to systemic absorption.
In the rat, the absorption of oestradiol-3-cyclopentyl ether administered in an aqueous solution was mainly via the bloodstream, but when the drug was given in sesame oil (primarily linoleic and oleic acid triglycerides) a greater proportion of the drug was absorbed by the lymphatic route98. Addition of glyceryl mono-oleate to the sesame oil augmented this effect. The lymphatic absorption of griseofulvin, a systemic antifungal agent, and probucol, a lipid-lowering agent, is also enhanced by food with high fat content, presumably by dissolution of the drug in the fat prior to absorption99 100. The natural extension of this is to dissolve the drug in a lipid administered as an emulsion, an approach which has proven useful with griseofulvin101.
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