Hepatic portal system, drug absorption

Absorption from the rectum depends on various physiological factors such as surface area, blood supply, pH, fluid volume, and possible metabolism by microorganisms in the rectum. The rectum is perfused by the inferior and middle rectal arteries, whereas the superior, the middle, and the inferior rectal veins drain the rectum. The latter two are directly connected to the systemic circulation the superior rectal vein drains into the portal system. Drugs absorbed from the lower rectum are carried directly into the systemic circulation, whereas drugs absorbed from the upper rectum are subjected to hepatic first-pass effect. Therefore, a high-clearance drug should be more bioavailable after rectal than oral administration. The volume of fluid in the rectum, the pH of that fluid, and the presence of stool in the rectal vault may affect drug absorption. Because the fluid volume is... 

Drug absorption may be variable depending upon the placement of the suppository or drug solution within the rectum. A portion of the drug dose may be absorbed via the lower hemorrhoidal veins, from which the drug feeds directly into the systemic circulation some drug may be absorbed via the superior hemorrhoidal veins, which feeds into the mesenteric veins to the hepatic portal vein to the liver, and metabolized prior to systemic absorption... 

Some drugs may be absorbed into the lymphatic circulation through the lacteal or lymphatic vessels under the microvilli. Absorption of drugs through the lymphatic system bypasses the first-pass effect due to liver metabolism, because drug absorption through the hepatic portal vein is avoided. The lymphatics are important in the absorption of dietary lipids and may be partially responsible for the absorption for some lipophilic drugs such as bleomycin or aclarubicin which may dissolve in chylomicrons and be systemi-cally absorbed via the lymphatic system. 

Hepatic avoidance using lymphatic output oral DDS. A liver-bypass drug delivery system that promotes absorption redistribution of lipophilic drug from the hepatic portal blood supply to the lymphatic system, thereby avoiding first-pass liver metabolism. 

The small intestine is drained by the hepatic portal vein, making the liver the first port of call for orally absorbed drugs. Therefore, high hepatic metabolism will compromise systemic availability. Formulation to enhance lymphatic absorption offers the potential for avoiding such first-pass metabolism. It could also target anticancer agents to lymphatic carcinomas. Table 1 lists various materials and associated therapeutic agents that have been formulated for lymphatic delivery. 

Following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination. The effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio (ER) ... 

The hepatic first-pass effect can be avoided to a great extent by use of sublingual tablets and transdermal preparations and to a lesser extent by use of rectal suppositories. Sublingual absorption provides direct access to systemic—not portal—veins. The transdermal route offers the same advantage. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, suppositories tend to move upward in the rectum into a region where veins that lead to the liver predominate. Thus, only about 50% of a rectal dose can be assumed to bypass the liver. 

All drugs administered to a patient are subject to biotransformation. Orally administered drugs are first subjected to metabolism by the intestinal epithelium and, upon absorption into the portal circulation, metabolized by the liver before entering the systemic circulation. While multiple tissues have certain degree of biotransformation capacity, it is generally accepted that hepatic metabolism represent the most important aspect of drug metabolism. 

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