Drug Metabolism Drug Metabolism
For example, the hydroxyl group can undergo glucuronic acid conjugation, sulfate conjugation and acetylation reactions. The amino group can be metabolised by glucuronic acid conjugation and acetylation. The human body is exposed to various foreign particles that are dust particles, food, toxins, and air pollutants. The term xeno means foreign, which is not a part of our body normally. When these foreign particles enter the body, the body has a mechanism to modify these particles so that they are excreted from the body. Drugs are also regarded as xenobiotics as drugs are foreign particles.
The process of amino acid conjugation occurs in those drugs which contain carboxylic groups. Glycine is the most important amino acid with which conjugation takes place but it also occurs with ornithine. In this reaction, there is the formation of a peptide bond between an amino acid and drug molecules. Amino acids are hydrophilic because they contain carboxylic and amino groups. First of all, drugs are converted into an activated form 14 (Figure 13). The carboxylic group of the drug reacts with ATP and the AMP ester of the drug is formed.
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- Usually, drugs lose pharmacological activity after oxidation but phenobarbital retains its activity after oxidation.
- Most Phase-I reactions, such as hydroxylation and heteroatom oxidation, represent relatively small structural modifications that primarily act to increase hydrophilicity and provide handles for further metabolism.
- The human body is exposed to various foreign particles that are dust particles, food, toxins, and air pollutants.
- Prescribers need to be aware of drug interactions with any of these enzymes that may alter responses to any other prescribed medications.
- The enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides.
Only small quantities of drugs are required to elicit the appropriate response. The four principal steps in drug metabolism studies are isolation (extraction), separation (chromatography), identification (spectrometry), and quantification of the metabolites. Detection systems are sensitive enough to allow the isolation and identification of submicrogram quantities of metabolites. The function of drug metabolism is to convert a molecule that can cross biological membranes into one that is cleared in the urine. is alcoholism a choice Each progressive metabolic step usually reduces the lipophilicity of the compound.
Anatomy and Physiology of the Liver
Second, because most drugs are lipid-soluble, biotransformation to more water-soluble products is necessary before they can be excreted in bile and/or urine. The metabolism of many substances occurs in two phases – oxidation (I) and conjugation (II) (Figure 2). 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.
Endogenous molecules are hydrophilic and increase the hydrophilicity of the drug. Phase II metabolic reactions decrease the affinity of the drug with the receptor and they are excreted from the body. The phase II reactions are collectively called conjugation reactions. Glucuronic acid conjugation, sulfate conjugation, amino acid conjugation, glutathione conjugation, acetylation, methylation are different types of phase II metabolic reactions. At one functional group, more than one conjugating enzymes can act.
If these substances decrease the ability of the enzymes to break down a drug, then that drug’s effects (including side effects) are increased. If the substances increase the ability of the enzymes to break down a drug, then that drug’s effects are decreased. The process of hydrolysis takes place in drug molecules which contain ester or amide linkage in their structure. Drug molecules like acetylcholine, suxamethonium, acetylsalicylic acid and procaine carry ester linkage in their scaffolds (Figure 9). Drug molecules having ether linkage in their structure undergo the process of oxidative dealkylation.
02.3.4 Metabolism
Examples of common Phase I (functionalization) and Phase II (conjugation) biotransformations that occur in drug metabolism. Drug metabolism typically results in the formation of a more hydrophilic compound that is readily excreted by the liver, kidney, and/or gut. The main families of CYP450 enzymes involved in drug metabolism are the monooxygenases of the CYP1, CYP2 and CYP3 families.
This difference was hypothesized to arise from differences in intramolecular hydrogen bonding that are possible between the two positional isomers. We recently characterized isomeric glucuronide metabolites of quercetin generated using human liver microsomes by TWIM-MS and computational modeling 48. At least two isomeric species were observed for quercetin glucuronide in multiple ionization states (M+H+, M+Na+), and computational modeling allows us to narrow down the potential assignments of positional isomers for each peak.
Further, unlike Phase I, Phase II reactions almost invariably inactivate a given drug. Cytochrome P450 enzymes are the main xenobiotic inactivators in humans. Therefore, liberty bells mushrooms esters are presented as prodrug form and amides can be presented as a slow-release drug.
Normally, the metabolism decreases pharmacological effect but sometimes metabolism produces dka breath smell toxic metabolites or active metabolites. Drugs which undergo metabolism to produce a pharmacological effect are called prodrugs. Some drugs undergo metabolism to produce toxic metabolites that are carcinogenic or mutagenic.