Drug absorption and avoidance of firstpass metabolism

Several factors have to be overcome for a drug to be absorbed after rectal administration. If the drug is administered as a suppository, melting or liquefaction of the base has to occur and the degree of this will partly determine the spreading of the dose through the rectum. The drug must then dissolve in the limited rectal fluid available, which has been estimated to be between 1 and 3 ml. The amount of drug available for absorption can be further reduced by degradation by luminal contents, adsorption to luminal contents and defaecation. The drug must then diffuse across the unstirred water and mucous layers adjacent to the epithelium.

Drugs may be absorbed across the epithelial cell or via tight junctions, and it is believed that only passive transport occurs. Venous return from the colon and upper rectum is via the portal vein to the liver. If a drug is delivered to the upper part of the rectum, it is transported into the portal system (Figure 7.10), and is therefore subject to first pass metabolism in the liver. The only way of avoiding first-pass metabolism is to deliver the drug to the lower part of the rectum. This simple principle is complicated by the presence of anastomoses which do not allow a precise definition of the areas which drain to the portal and systemic circulation. A 100% increase in the availability of lignocaine was demonstrated when administered rectally rather than orally, and it was calculated that the mean fraction of the rectally administered dose escaping first-pass metabolism was 57%113. Other drugs with high first pass metabolism, such as salicylamide and propranolol, did not demonstrate as large an increase in bioavailability when administered rectally. However, this may be due to incomplete absorption since these drugs exhibited a much larger bioavailability when administered rectally rather than orally to rats114.

Figure 7.10 Structure and perfusion of the rectum

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