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Drug Metabolism and Drug Metabolism Principles - Phase I and Phase II

The process of biotransformation of medications in the body so that they may be readily removed is referred to as drug metabolism.

Drug Metabolism

The process of biotransformation of medications or non-essential foreign chemicals in the body so that they may be readily removed is referred to as drug metabolism. It is essentially a method of incorporating a hydrophilic moiety into a medicinal molecule in order to ease excretion.

The liver is the principal site of drug metabolism. Although drug metabolism normally renders pharmaceuticals inactive, some drug metabolites are pharmacologically active—sometimes much more so than the parent substance. A prodrug is an inert or weakly active molecule that contains an active metabolite, especially if it is designed to deliver the active moiety more efficiently.

The purpose of metabolizing a drug is to make it more excretable. Chemical transformations include oxidation, reduction, hydrolysis, hydration, conjugation, condensation, and isomerization. The enzymes involved in metabolism can be found in a variety of tissues, although they are most concentrated in the liver. The rates of drug metabolism differ amongst patients. Several people have so fast metabolism that they do not achieve therapeutically effective blood and tissue concentrations; others have such a delayed metabolism that they are unable to take standard dosages. All of these factors can affect individual drug metabolism rates, especially those involving induced or inhibited metabolisms (especially with chronic liver disease and severe heart failure).

Metabolism of many medicines happens in two stages. Non-synthetic phase I reactions include the oxidation, reduction, and hydrolysis of functional groups and groups. Synthetic Phase II reactions require conjugation with an endogenous molecule (e.g., glucuronic acid, sulphate, glycine). Synthetic metabolites are more easily eliminated by the kidneys (in urine) and the liver (in bile) than non-synthetic substances. Because certain drugs only elicit phase I or phase II responses, phase numbers are used to classify pharmaceuticals functionally rather than sequentially.

Hepatic drug transporters are located in all parenchymal liver cells and have an impact on drug distribution, metabolism, and excretion in the liver]. Ingress transporters transfer substances into the liver, whereas efflux transporters mediate drug excretion into the blood or bile. Hepatic drug transporter expression and function can be altered by genetic polymorphisms in a number of ways, potentially affecting a patient's susceptibility to pharmaceutical side effects and drug-induced liver injury. Carriers of particular transporter genotypes have greater blood levels of statins and are more susceptible to statin-induced myopathy when statins are taken to treat hypercholesterolemia.

Site of metabolism

Various enzymes found in the liver are required for the metabolism of medications and foreign substances (collectively referred as xenobiotics). Liver illness should have a significant impact on medication metabolism and drug duration. Some medications' elimination half-life is affected by liver illness. Despite the fact that the liver is the principal site of metabolism, all tissue cells contain some metabolic activity. Other metabolically active organs include the gastrointestinal system, kidneys, lungs, skin, plasma, and nerve tissue.

Pathways for drug metabolism



Phase I reactions

It is a common biotransformation route. Reactions in phase 1 are predominantly oxidative (aromatic and aliphatic hydroxylations, N.,0-, S-dealkylations, N-hydroxylations, sulfoxidations, deaminations, and dehalogenations), as well as reduction (azodye reductions and nitrogen reductions).

N – hydroxylations



Noxidation



S – Oxidation



N – dealkylation



O – dealkylation



S – dealkylation



Reduction



Phase II reactions

Phase II biotransformation processes (also known as 'conjugation reactions') function as a detoxification stage in the metabolism of pharmaceuticals, other xenobiotics, and endogenous substrates. On the other hand, due to the metabolic synthesis of hazardous metabolites such as reactive electrophiles, these conjugations play an important part in the toxicity of numerous substances.

Conjugation reactions are divided into two groups based on whether or not a high–energy intermediate is used to activate the metabolite.
  • Type I (glucuronidation and sulfonation, for example), in which an active conjugating agent reacts with the substrate to give the conjugated product, and type II (e.g., sulfonation).
  • Type II (for example, amino acid conjugation), in which the substrate is activated before being linked with an amino acid to generate a conjugated product.


Glucuronidation of sulphilamide and cyproheptadine

Sulphate conjunction



Amino acid conjunction



Glutathione conjunction



Methylation


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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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