Author: Alex Thompson

Drug Metabolism StatPearls NCBI Bookshelf

These drug metabolites may either be inactive or they may be similar or different from the original drug (parent drug) in terms of toxicity or therapeutic activity. The body becomes accustomed to the constant presence of the drug and compensates by increasing the production of enzymes necessary for the drug’s metabolism. This contributes to pharmacological tolerance and is one reason patients need ever-increasing doses of certain drugs to produce the same effect. The metabolism of drugs can occur in various reactions, categorized as phase I (modification), phase II (conjugation), and in some instances, phase III (additional modification and excretion). Glucuronidation is the most common type of phase II reaction, and occurs in the microsomal enzyme system of the liver. This reaction increases the solubility of the drugs so that they can be secreted in the bile or urine.

(See also Introduction to Administration and Kinetics of Drugs.) All drugs are eventually eliminated from the body. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached; in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism). Phase III metabolism may also follow phase II metabolism, in which conjugates and metabolites are excreted from the cells.

Factors affecting drug metabolism

Consequently, newborns and older people often need smaller doses per pound of body weight than do young or middle-aged adults. The most important enzyme system of phase I metabolism is cytochrome P-450 (CYP450), a microsomal superfamily of isoenzymes that catalyzes the oxidation of many drugs. The electrons are supplied by NADPH–CYP450 reductase, a flavoprotein that transfers electrons from NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) to CYP450. After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates.[11] Here, the γ-glutamate and glycine residues in the glutathione molecule are removed by gamma-glutamyl transpeptidase and dipeptidases.

The higher concentration of the drug in the body creates a greater potential for adverse effects. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound.[1] Useful metabolites are excluded since they are polar, and in general contain one or more charged groups. Drug metabolism is an essential clinical concern for the interprofessional healthcare team.

These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). Interprofessional team interventions are an effective part of medication management through interventions and monitoring.

Permeability barriers and detoxification

During reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion). Some metabolites stay in the body long after the parent drug has been expelled from the system. Therefore, there is a higher probability of getting a positive result by looking for the metabolites instead of the parent drug. In the drug testing industry, many drug tests will look for the presence of certain drug metabolites as a reliable indicator that a person used the “parent drug” of that metabolite. This insightful interview explores the disparities in neurological care and the innovative strategies aimed at transforming research and treatment for better, inclusive health outcomes. Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy.

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2), and thiol (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites. The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems.

In some cases, therapeutic doses of the drug can lead to the saturation of the enzyme sites. In such cases, the metabolism remains constant despite increases in the dose of the drug. Because metabolic enzyme systems are only partially developed at birth, newborns have difficulty metabolizing certain drugs. As people age, enzymatic activity decreases, so that older people, like newborns, cannot metabolize drugs as well as younger adults and children do (see Aging and Drugs Aging and Medications ).

1. Hologic, Inc. is a global medical technology innovator primarily focused on improving women’s health and well-being through early detection and treatment.
2. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them.
3. Drug metabolism is an essential clinical concern for the interprofessional healthcare team.
4. However, when most of the enzyme sites are occupied, metabolism occurs at its maximal rate and does not change in proportion to drug concentration; instead, a fixed amount of drug is metabolized per unit time (zero-order kinetics).
5. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this.

The majority of metabolic processes that involve drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated there. The liver’s main metabolizing agent is a specific group of cytochrome P-450 enzymes. These enzymes have a limited capacity so when levels of a drug in the blood are high, the enzymes become overloaded. Many other substances like food and other drugs affect these cytochrome P-450 enzymes. When they are at decreased ability to break down a drug, that drug’s side effects are increased.

When drugs get into the liver, enzymes will convert pro drugs into active metabolites or convert active drugs into their inactive form. Drug metabolism on the other hand specifically refers to the chemical alteration that any drug undergoes inside the body. This alteration results in other substances called drug metabolites.

Phase III – further modification and excretion

Hepatic drug transporters are present throughout parenchymal liver cells and affect a drug’s liver disposition, metabolism, and elimination (for review, see [ 1, General references The liver is the principal site of drug metabolism (for review, see [ 1]). Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even… The 2 primary types of transporters are influx, which translocate molecules into the liver, and efflux, which mediate excretion of drugs into the blood or bile. The substances that result from metabolism (metabolites) may be inactive, or they may be similar to or different from the original drug in therapeutic activity or toxicity.

Conversely if other substances increase the ability of the enzymes to break down a drug, that drug’s side effects are decreased. The most common and important enzyme group involved in the Phase I metabolism of drugs is the cytochrome P450 (CYP450) superfamily of enzymes. This group of enzymes acts as a catalyst for the oxidation of many drugs. It can, in turn, also be induced or inhibited by many drugs and other substances. As a result, the metabolism of some drugs is affected by the presence of other substances. However, the metabolites of some drugs are pharmacologically active and exert an effect on the body.

The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes. The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized. The capacity of the enzymes to metabolize is limited, so they can become overloaded when blood levels of a drug are high (see Genetic Makeup and Response to Drugs Genetic Makeup and Response to Drugs ). Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver.

Drug metabolism

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