MCAT Biological and Biochemical Foundations of Living Systems: Passage 12 — Flashcards

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The typical route of absorption of orally administered drugs is via intestinal cells called enterocytes. Drugs are transported across these cells and in most cases then diffuse into the portal vein, which brings blood from the intestines to the liver. Absorption through this route, however, involves first-pass metabolism through the liver, which significantly reduces the concentration of the drug that makes it into systemic blood. An alternative route that avoids this effect is for drugs to enter lymphatic vessels after transport across enterocytes. There is a dense layer of blood and lymphatic vessels underlying enterocytes of the gastrointestinal tract, yet because of the higher flow rate of portal blood, the majority of compounds take this route. However, there are drug properties that can encourage lymphatic drug uptake. For example, the diffusion of drug molecules across the blood vessel endothelium can get blocked, and as a result intestinal lymph transport is favored because lymphatic capillaries are more permeable than blood capillaries. In addition, the association of drug compounds with lipoproteins in enterocytes not only facilitates their transport through these cells but also preferentially releases them into lymphatic vessels because they are too big to diffuse into blood vessels. As a result, lipophilic drugs, such as cyclosporine, halofantrine, and testosterone derivatives, have lymphatic transport, which studies have shown contribute to their bioavailability. In contrast, hydrophilic drugs, such as caffeine and salicylic acid, are primarily taken up by blood vessels.

The type of lipid determines the lipophilicity of the compound: fatty acid chains with more than 14 carbons are more lipophilic than shorter chains, and unsaturated fatty acids are more likely to undergo lymphatic transport than saturated fatty acids. Many drugs have been modified with these types of lipids to improve bioavailability. For example, a study of the HIV drug didanosine conjugated the compound to triglycerides. Even though lipid modifications have been found to adversely affect activity for other drugs, the study found that triglyceride derivatives of didanosine did not become significantly more toxic to peripheral blood mononuclear cells in culture, based on CD50 values, which is the concentration of drug at which half of the cells die. In addition, the derivates were similar to unmodified didanosine in their effective dose, or ED50 values, which in this case is the concentration of drug that inhibits viral reverse transcriptase activity. In addition to boosting better bioavailability, HIV drugs that have increased lymphatic transport could be especially effective against this virus because it has been suggested that the gut lymphatic system is critical in the development of infection. Several other viruses are also thought to spread through the lymphatic network, such as hepatitis B, hepatitis C, and severe acute respiratory syndrome. This network is also the primary route for transport of B and T cells, as well as metastasis of solid tumors. Thus, immunomodulatory compounds and anticancer drugs could also be effective if they were absorbed lymphatically.