Drug Metabolism Principles- Phase I And Phase II Reactions

Introduction

The drug is eliminated irreversibly from the body by two processes, one is metabolism and other is excretion. The process of biotransformation of drugs or non-essential foreign chemicals in the body, to remove out of the body this process is referred as drug metabolism. Unabsorbed drug or non-essential chemical is made hydrophilic to remove it through excretion. Human body can detoxify foreign chemicals (xenobiotics), carcinogen and toxins. The ability of human body to metabolise and eliminate drugs and xenobiotics is a natural process, which involves some enzymatic pathways and transport systems. In this article we will see drug metabolism, drug metabolism principles – phase I and phase II reactions, factors affecting drug metabolism.

Table of Contents

Drug metabolism

The liver is the principal site for drug metabolism. Typically, metabolism inactivates the drug but some drug metabolites are pharmacologically active, sometimes even more active than parent compound. Drugs can be metabolised by oxidation, reduction, hydrolysis, hydration, conjugation, condensation or isomerisation. The enzymes involved in metabolism process are present abundantly in liver.

Metabolism reactions produce more polar, inactive metabolite so that they are readily excreted from the body. Drug metabolism is classified into two types,

Phase I/ functionalisation reaction/ non-synthetic reactions
Phase II/ conjugation reaction/ biosynthetic reaction

Phase I reactions

This type of drug metabolism is catalysed by various enzymes. These enzymes either adds or exposes a functional group, allowing the products of phase I metabolism to serve as substrates for phase II reaction. Phase I reactions are carried out by,

Cytochrome P-450 enzyme (CYP-450)
Flavin containing monooxygenase
Epoxide hydrolases

Cytochrome P-450 enzyme (CYP-450) superfamily

The CYPs are superfamily of enzymes which contain haeme molecule, which is non-covalently bound to the polypeptide chain. More than 50 individual CYPs have been identified in humans. Out of these, 3 main CYP families (CYP1, CYP2 and CYP3) are involved in the drug metabolism. CYP3A4 enzyme involved in the metabolism over about 50% of clinically used drugs. In the CYP3A4 enzyme 3 stands for family, A stands for subfamily, 4 stands for gene number. CYPs are mainly located in liver, also found in GIT, in lower amounts in lungs, kidneys and CNS.

CYPs have capacity to metabolise drugs because of their large and fluid binding sites. CYPs can metabolise diverse reactions due to,

Multiple form of CYPs
The capacity of single CYP to metabolise many structurally different drugs and xenobiotics
A single compound can also be metabolised by different CYPs

Phase I metabolites have enzymes specific interactions. Overlapping substrate specificity of enzyme may lead to slowing metabolic rate or drug-drug interactions.

CYPs and drug-drug interaction

Drug-drug interactions commonly inhibits the drug metabolism by CYPs but sometimes they may induce enzyme actions. The action of enzyme is increased mostly by transcriptional activation, which increases synthesis of more CYP enzyme proteins.

The enzyme activity can be inhibited by following mechanisms,

Competitive inhibition: When two drugs metabolised by same CYP enzyme. Example, simvastatin and erythromycin.
Non-competitive inhibition: When drug molecule bounds to enzyme. Drug molecule loss its activity. Example, ketoconazole forms a tight complex with haeme moiety of CYP3A4.

Drug-drug interactions commonly occur when two or more drugs are administered simultaneously and their metabolism is catalysed by same enzyme. Thus, it is important to avoid co-administering drugs which are metabolised by same enzyme.

CYP enzyme inhibitors	CYP enzyme inducers
Cimetidine	Barbiturates
Some macrolides	Carbamazepine
Some antifungals	Phenytoin
Some 4-quinolones	Rifampicin
Some HIV agents	Ethanol (CYP2E1)
Grapefruit juice	Cigarette smoke

Flavin-containing monooxygenase (FMOs)

The flavin containing monooxygenase (FMO) protein family metabolises the drugs and xenobiotics which facilitate the excretion. These enzymes can oxidise a wide range of drugs like amines, sulphides and phosphates. The FMOs share the same activity profile as that of CYP450 enzymes. The major difference between these two-enzyme family is, CYP enzymes uses oxygenated haeme group while FMO family utilizes flavin adenine dinucleotide (FAD) to oxidize its substrates.

Phase II reactions

In phase II reactions drugs and xenobiotics are conjugated with charged species like glutathione (GSH), sulphate, glycine or glucuronic acid. Products of conjugation reaction have increased molecular weight and are less active. Phase II reactions are catalysed by broad specificity transferases enzymes. These group of enzymes can metabolise hydrophobic compound. One of the most important class of these group is glutathione S-transferases (GSTs).

Conjugation reactions can be divided into two types, based on whether or not high energy intermediate is used to activate the metabolite.

Type I: In this type conjugating agent reacts with the active substrate to give conjugated product. For example, sulphonation
Type II: In this type substrate is activated before binding with amino acids to produce conjugated metabolite. For example, amino acids conjugation.

First pass metabolism

It is the metabolic inactivation of a significant proportion of an orally administered drug before the drug reaches to the systemic circulation. The first pass metabolism occurs either at the intestinal epithelium or at the liver. It significantly limits the oral bioavailability of highly metabolised drugs. Due to this a much larger dose of the drug is needed when it is given orally as compared to administered parentally. Some examples of drugs which undergo first pass metabolism are, aspirin, metoprolol, glyceryl trinitrate, morphine, propranolol, levodopa, salbutamol, verapamil, etc.

Summary

The principles of drug metabolism involve the body’s processes of converting drugs into more water-soluble forms to facilitate elimination. This primarily occurs in the liver through two main phases, phase I reactions which involve modification of the drug molecule, and phase II reactions which involve conjugation to enhance water solubility. Enzymes, particularly those in the cytochrome P 450 family, play a crucial role in these processes. Understanding drug metabolism is vital for predicting drug interactions, optimising therapeutic effects and avoiding potential adverse reactions.

Frequently asked questions

What is prodrug?

The prodrug is a pharmacologically inactive compound, which after intake is metabolised into a pharmacologically active drug. Example, aspirin, irinotecan, codeine, heroine, levodopa, etc.

What are xenobiotics?

Xenobiotics are the chemical substances which are foreign to human body. Xenobiotics is derived from Greek words, xenos means foreigner or stranger and bios means life. Example, drugs, plant constituents, cosmetics, pesticides, fragrances, food additives, etc.

What is the principal site of drug metabolism in the body?

The liver is the principal site of drug metabolism.

What are the two main types of drug metabolism?

Two main types of drug metabolism are, phase I (modification) and phase II (conjugation).

What is the first pass metabolism?

First pass metabolism is the pharmacological phenomenon in which a drug undergoes metabolism before going to systemic circulation. First pass metabolism occurs at the liver or intestinal endothelium.

Drug Metabolism Principles- Phase I and Phase II Reactions