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Let’s trace the path and fate of an oral drug in the body. Along the way we will both define and use some of our terminology. So, an oral drug starts by going into a patient’s mouth. The drug travels into the stomach and then the small intestine. Depending on the properties of the drug, it may cross the lining of the stomach and/or the small intestine and enter the blood of the hepatic portal system. This process is called absorption – the A in ADME. If any drug is not absorbed, it will simply exit the body in the feces. The blood in the hepatic portal system enters the liver, which is rich in metabolic enzymes. Some drug may be chemically modified and broken down in the liver. This is metabolism – the M in ADME. Metabolism can occur in other organs and tissues, but the liver is the main site of metabolism. That is hepatic metabolism. It is worth noting that the intestinal lining is also rich in metabolic enzymes, and metabolism in the intestinal wall can reduce absorption. OK, once the drug passes through the liver, it will reach the general circulation. From the general circulation, the drug will have access to all other parts of the body. At this point the drug will undergo distribution – the D in ADME – distribution to and from all parts of the body. That generally includes the drug target, the intended site of action of the drug. As the drug circulates in the body, it will sometimes pass through the liver. With each pass through the liver, more drug will be metabolized and the plasma concentration will be reduced. The drug will sometimes pass through the kidneys, where it may be filtered from the blood and excreted, specifically renal excretion. Excretion is the E in ADME. With each pass through the kidneys, more drug may be excreted, and the plasma concentration will be reduced. Other organs can excrete drugs, but the kidneys are the main site of excretion. Both metabolism and excretion reduce plasma concentration and are processes for the elimination of a drug. All the different facets of ADME – absorption, distribution, metabolism, and excretion – affect the pharmacokinetics of a drug, namely the half-life. During drug discovery, considerable effort is expended to understand the ADME properties of a molecule through relatively rapid and simple in vitro tests to make sure that only the molecules with likely favorable PK properties will be advanced into in vivo studies.

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