metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. generally, drug metabolism begins with hydrophobic drug and converts it to a more hydrophilic metabolite to facilitate its elimination.
an understanding of the drug metabolism process and the potential outcomes is critical for developing safe and useful pharmaceuticals.
drug metabolism can result in one of two products, an inactive metabolite and an active metabolite.
inactive metabolites of the drugs basically have no pharmacological activity of the original drug. an example of that would be the hydrolysis of procaine into para aminobenzoic acid and diethylethanolamine which results in the loss of the anesthetic activity of procaine.
on the other hand, an active metabolite can mean that a metabolite can retain the same activity of the parent drug, that's apparent when codeine is demthylated to a more active drug which is morphine.
however, in some cases we notice a result known as bioactivation where the parent drug is inactive and the metabolite would have a pharmacological activity, in this case the inactive parent drug is called a prodrug.
an example of a prodrug is enalapril which has no activity as an antihypertensive, but upon hydrolysis it becomes enalaprilat which is a potent antihypertensive drug.
bioactivation of a drug can also lead to toxic metabolites, the widely used acetaminophen has a metabolite that is called n-acetyl-p-benzoquinone imine which is hepatoxic, I explained the mechanism of the toxicity and the antidote in my previous video which I linked in the description below.
The liver has the highest concentration of drug-metabolizing enzymes, because of it’s location between the gastrointestinal tract and the systemic circulation.
Based on the reactions involved in the metabolism process we can classify the metabolic pathways into phase I metabolism and phase II.
Phase I metabolism is characterized as a functionalization reaction, where they add or reveal a functional group by oxidation, reduction, or hydrolysis, hence, leading to increase in overall polarity of the drug which facilitates its excretion in the urine
Oxidation is the most common phase I reaction,
Cytochrome p450 is a superfamily of oxidases that are responsible for the majority of oxidation reactions, it’s found in very high concentrations in the liver.
Oxidation can also happen through alcohol dehydrogenase which is an enzyme that oxidizes alcohols into aldehydes from primary alcohols and to ketones from secondary.
Aldehydes can be oxidized from to carboxylic acid by the enzyme aldehyde dehydrogenase. We can see that in the example of the conversion of acetaldehyde to acetic acid in the metabolism of ethanol.
Another phase I reaction is the reduction reaction, there are several reductase enzymes common reduction reactions include the reduction of disulfide bonds, in which the disulfides would be reduced to free sulfhydryls. Another reduction reaction is done by the aldo-keto reductases which reduce carbonyl containing compounds back to alcohol in a process opposite to the oxidation done by alcohol dehydrogenase.
The last type of phase I metabolism reaction is hydrolysis, hydrolysis is basically the addition of water across a bond resulting in a more water-soluble metabolite. A great example of hydrolysis is ester hydrolysis which is performed by the enzyme esterase found throughout the body, esterase is responsible for the hydrolysis of an ester into a more soluble alcohol or carboxylic acid.
Phase II reactions are commonly called conjugation reaction owing to the fact they add a functional group on the drug for the purpose of increasing its polarity. The conjugation process requires an enzyme generally termed as transferase, that transfers the large polar molecule called a co-factor onto the drug,
Examples of phase II reactions:
glucuronidation is the most common phase II reaction, glucuronosyltransferase is the enzyme that uses UDP-GA as the cofactor to transfer glucuronic acid to several functional groups like hydroxyl groups, carboxylic acid ,and hydroxylamines. The glucuronic acid adds a significant amount of hydrophilicity to the molecules facilitating it’s excretion process.
Another popular reaction is glutathione conjugation which results from the addition of glutathione molecule to an electrophilic substrate. Being a nucleophile glutathione generally acts to detoxify electrophiles.
Glutathione-s-transferase is the enzyme responsible for the reaction of glutathione with electrophiles like epoxides and halides. After the conjugation, the product is excreted as mercapturic acid in the urine.
Paracetamol antidote video: https://www.youtube.com/watch?v=hg_gpWjWsRM