The main organ for drug metabolism is

We all know that the residues in food that are not absorbed by us will be excreted, but many people don’t know much about the organs that handle drug metabolism. The organs that process drug metabolism are the liver and intestinal wall. Our liver is responsible for processing toxic substances in the body. Many of the enzymes secreted by the liver are mainly for drug metabolism. The drugs we take orally or inject enter our body in two stages: the first is decomposition and oxidation, and the second is combination with anion groups in the body.

Drug metabolism refers to the process in which the chemical structure of a drug changes under the action of various drug-metabolizing enzymes in the body (especially liver drug enzymes), also known as biotransformation or drug metabolism. The biotransformation and excretion of drugs are called elimination. There are two results of drug biotransformation in the body: one is inactivation, becoming a pharmacologically inactive drug; the other is activation, from a pharmacologically inactive drug to a pharmacologically active metabolite or the production of toxic metabolites, or the original pharmacological effect is retained after metabolism. Therefore, biotransformation cannot be called a detoxification process.

The liver is the main organ for drug clearance, and liver clearance is divided into two modes: liver metabolism and biliary excretion. The liver is rich in various enzymes required for phase I and phase II metabolism of drugs, among which P450 enzymes are the most important. P450 enzymes are a large family composed of various types of P450 enzymes. According to the similarity of the amino acid sequence, P450 enzymes can be divided into several different categories, and each category can be further divided into several subcategories. The important P450 enzymes in humans are CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. There are obvious species differences in P450 enzymes, and the metabolic pathways and metabolites of drugs in animals and humans may be different. Polymorphism is an important characteristic of P450 enzymes and an important cause of individual differences in drug response. The so-called polymorphism refers to the large difference in the amount of a certain P450 enzyme between different individuals of the same species. Individuals with high levels of metabolic rate have a fast metabolic rate and are called extensive metabolizers; individuals with low levels of metabolic rate have a slow metabolic rate and are called poor metabolizers. Many P450 enzymes in the human body show polymorphism, among which the polymorphisms of CYP2D6 and CYP2C19 are the most typical. In addition, P450 enzymes are both inducible and inhibitory. That is, the amount and activity of P450 enzymes can be affected by drugs (or other xenobiotics), which may affect the metabolism of the drugs themselves and may cause metabolic drug interactions.

In recent years, studies have found that many drugs are metabolized when passing through the intestinal wall after being absorbed in the small intestine, resulting in reduced bioavailability of the drugs. This first-pass effect in the intestine has attracted considerable attention. The epithelial cells of the intestinal lining move from the lower end of the villi to the top and then fall off. During this process, the epithelial cells gradually mature, and the whole process takes about two or three days. Drug-metabolizing enzymes in the intestinal wall are mainly distributed in mature epithelial cells, among which the villus tips are the most active. Many types of metabolic enzymes have been found in the intestinal wall, such as CYP26, CYP2C9, CYP2C19, CYP3A4, CYP3A5, etc., among which CYP3A4 has the highest content (ref1). Many drugs commonly used in clinical practice are substrates of CYP3A and can be metabolized in the intestinal wall. Intestinal wall metabolism is one of the important reasons for the low oral bioavailability of many drugs.

Drug metabolism reaction types Drug metabolism usually occurs in two stages. The first stage is usually oxidation, reduction and hydrolysis reactions; the second stage is conjugation reaction. But in order to bind, the molecule must have an anionic group that can react with the binding substance. Many drugs do not originally have these groups, and the first stage of the reaction is to expose or introduce these groups such as -OH, --COOH or -NH2. Different drugs are metabolized in different ways. Some drugs only need to undergo one type of chemical change, while most drugs need to undergo a two-stage reaction. In short, whether it is a one-stage or two-stage reaction, its purpose is to convert the compound into a form that is more soluble in water and easier for the kidneys to excrete.