Drug Metabolism: Phase I and Phase II Metabolic Pathways
Genetic variations in how certain drugs (for example, statins) are transported into and out of the liver may increase a person’s risk of drug side effects or drug-related liver injury. This webpage produced by Indiana University Department of Medicine lists clinically relevant CYP450 enzyme substrate drugs, and drugs which either inhibit or induce CYP450 activities, tabulated against the corresponding enzyme subtype. The most important difference between Phase I and II reactions is that the former one is molecule-autonomous whereas the latter one creates a covalent bond with another molecule or its part.
3 Amino acid conjugation
Drugs which are metabolised by sulfate conjugation are endogenous steroids, catecholamines and other neurotransmitters. Therefore, when a drug is administered for a longer time, then sulfate ions are depleted from the body. In this way, the process of glucuronic acid conjugation dominates 13. drinker nose Drug molecules which contain reducible groups like nitro, azo, alkene, aldehydes, and ketones easily undergo the process of reduction. The process of reduction is catalysed by specific enzymes which catalyse the reduction for specific classes. The nitro reductase is required for the reduction of the nitro group.
Phase III – further modification and excretion
Consequently, newborns and older people often need smaller doses per pound of body weight than do young or middle-aged adults. Drug metabolizing enzymes have evolved primarily as a defense against non-medical chemicals taken up from the environment. They are therefore expressed also at other interfaces of the body with the environment such as the skin, lungs, and the kidney.
- Sulfotransferases are also present in the intestine, brain and platelets of blood.
- But it was proved that phenacetin is converted into acetaminophen in the body by oxidative dealkylation which is a safer drug than phenacetin.
- Examples of N-methylation are conversion of noradrenaline into adrenaline, and histamine into n-methyl histamine.
- Drug metabolism (biotransformation) produces metabolites with different physicochemical and pharmacological properties from the parent drug molecule.
- The study of drug metabolism is essential for the safety and efficacy of drug molecules.
Knowledge of drug metabolism is important in optimizing the use of drugs, maximizing benefits and minimizing harms. Drug metabolism, also known as xenobiotic metabolism, is the biochemical modification of pharmaceutical substances or xenobiotics respectively by living organisms, usually through specialized enzymatic systems 14. These are non-synthetic reactions that introduce a hydrophilic group or unmask the already present hydrophilic group in these drugs.
Determination of drugs and drug metabolites by ion mobility-mass spectrometry: A review
For example, chloramphenicol palmitate and bacampicillin are prodrugs of chloramphenicol and ampicillin respectively. The process of acetylation takes place in those drugs which contain amino group, hydrazine and hydrazide linkage in their structures. In the process of acetylation, the amino group is converted into an amide group. The acetyl co-enzyme A is formed by pyruvic acid, the end product of glycolysis 18. Generally, phase II what are whipits reaction increase the hydrophilicity of drugs but the acetylation does not increase hydrophilicity.
The substrate promiscuity of DMEs often means that for a particular parent compound, multiple isomeric metabolites may be generated from different sites of metabolism. These isomeric metabolites are isobaric and thus indistinguishable by MS alone; however, they have different structural characteristics and depending on the magnitude of such differences, they may be resolvable in IMS. Separation of positional isomers is thus an important application in the determination of drug metabolites by IM-MS. For meeting regulatory submission expectations and validating important actors in the metabolism of drugs, specific drug metabolism research has been carried out. Drug metabolism or drug biotransformation is the process by which xenobiotics are enzymatically modified to make them more readily excretable and eliminate pharmacological activity. Drug metabolism is affected by age, environmental factors, disease and genetics.
While the majority of drug metabolism results in less toxic metabolites, occasionally it can result in the formation of more toxic compounds. A large number of drugs are metabolized by hepatic phase I and II reactions. Drug metabolism is an important process for the removal of unwanted substances from the body. Abnormal drug metabolism profile could lead to life-threatening complications. Both phase I (mainly CYP450s) and phase II (mainly UGTs) enzymes play a significant role in drug metabolism.
In this situation, the body is exposed to the harmful effects of these metabolites. This conjugation reaction is a displacement or substitution reaction. When a drug is metabolised by glutathione conjugation it is not excreted from the body and it is further converted into mercapturic acid which is the end product. In this step, glutamic acid and glycine are cleaved from glutathione. The metabolism of drugs within the liver occurs in two stages in most instances.
For example, the conversion of morphine into morphine 6-glucuronide. When the conjugation occurs at position 6, a pharmacologically active metabolite is produced. Most of the drugs undergo glucuronic acid conjugation and it is the most important amongst phase II metabolic reactions.
Phase I metabolic reactions introduce a hydrophilic group in the drug molecules where phase II metabolic reactions can take place. In this chapter, we discussed the drug metabolic reactions and enzymes involved in these reactions. The study of drug metabolism is list of foods that contain alcohol essential for the safety and efficacy of drug molecules. The pharmacokinetic properties of drugs can be predicted by carrying out drug metabolism studies. The metabolic pathways of new drugs should be determined to predict the possibility of adverse drug reactions and drug-drug interactions. The process of glucuronic acid conjugation usually terminates the pharmacological activity of drugs but in some cases drug is converted into an active form.