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Our Presentation Topic Is:

Drug metabolism and The concept of pro-drugCourse name : Medicinal chemistry-I

Course code: BPH-232

Course teacher: Md. Abdullah Aziz

Name Of Our Group Members:

Name ID

Bisshojit Biswas BPH 051 06831

Drug Metabolism: Definition Drug metabolism also known as xenobiotic metabolism is the biochemical modification of pharmacological substances or xenobiotics respectively by living organisms, usually through specialized enzymatic systems. Drug metabolism often converts lipophilic chemical compounds into more readily excreted hydrophilic products. The rate of metabolism determines the duration and intensity of drug’s pharmacological action.Xenobiotic came from the Greek word xenos mean “stranger” and biotic mean “related to living beings”.

Drug Metabolism: (Xenobiotic Metabolism)Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons.These pathways are a form of biotransformation present in all major groups of organisms, and considered to be of ancient. These pathways are of particular interest in medicine as part of drug metabolism and as a factor contributing to multidrug resistance in infectious diseases and cancer chemotherapy.

Drug Metabolism: Phases There are three phases of drug metabolism. They are- Phase I: In phase I, enzymes such as

cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics.

Phase II: These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalyzed by transferase enzymes such as glutathione S-transferases.

Drug Metabolism: Phases

Fig: Phase I and II of the metabolism of a lipophilic xenobiotics Phase III: Finally, in phase III, the conjugated xenobiotics

may be further processed, before being recognized by efflux transporters and pumped out of cells.

Drug Metabolism: Phases

Fig: Cytochrome P450 oxidases, which are important enzymes in xenobiotics metabolism.

Drug Metabolism: Permeable Barriers All organisms use cell membrane as hydrophobic

permeability barriers to control access to their internal environment polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated through transport proteins and substrate is selected specifically from the extracellular fluid. As a result hydrophilic molecules cannot enter the cell, because they are not recognized by any specific transporters. On the other hand, diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers.

Drug Metabolism: Permeable Barriers However, the existence of a permeability barrier

means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolize almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.

 

Drug Metabolism: Factors That Effect Drug MetabolismThe duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system is the most important pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition). However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can speed up this conversion and increase drug levels, potentially causing toxicity. 

Drug Metabolism: Factors That Effect Drug MetabolismVarious physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include – Age, Individual variations (e.g. pharmacogenetics), Enterohepatic circulation, Nutrition, etc.In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults.

Prodrug: Definition

A prodrug is a medication that is administered in an inactive or less than fully active form, and is then converted to its active form through a normal metabolic process, such as hydrolysis of an ester form of the drug.According to IUPAC: Compound that undergoes biotransformation before exhibiting pharmacological effects.

Prodrug: Importance A prodrug is a precursor chemical compound of a

drug. A prodrug is used instead of the drug to improve

absorption, distribution, metabolism, and excretion (ADME).

Prodrugs are important for improving bioavailability ; when the drug itself is poorly absorbed from GIT.

Prodrugs are important for improving the interaction of the drugs with the cells

The using of prodrugs reduces unintended side effects of a drug, which is important in treatment like chemotherapy.

Prodrug: Classification

Based on how the body converts the prodrug into the final active drug form, the prodrugs have been classified into two major types. They are- Type I: Prodrugs are bioactivated intracellularly. Type II: prodrugs are bioactivated extracellularly,

especially in digestive fluids or in the body's circulation system, particularly in the blood.

Prodrug: Classification (Type I & Type II Examples)

Type I:Examples of these are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering statins.

Type II: Examples of Type II prodrugs are salicin and certain antibody-, gene- or virus-directed enzyme prodrugs used in chemotherapy

Prodrug: Classification (Sub classification)Both major types can be further categorized into subtypes, based on factors such as, in case of type I-Whether the intracellular bioactivation location is also the site of therapeutic action.In case of type II-Whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation systemTherefore, Type I (A):prodrugs include many antimicrobial and

chemotherapy agents (e.g., 5-flurouracil).

Prodrug: Classification (Sub classification) Type I (B):This type of prodrug agents rely on

metabolic enzymes, especially in hepatic cells, to bioactivate the prodrugs intracellularly to active drugs.

Type II (A): This type of prodrugs are bioactivated extracelluarly, either in the milieu of GI fluids.

Type II (B): This type of prodrugs are bioactivated within the systemic circulation and other extracellular fluid compartments .

Type II (C): This type of prodrugs are bioactivated near therapeutic target tissues/cells.

Prodrug: Classification (Sub classification)

All the prodrugs in type II subclasses rely on common enzymes such as esterases and phosphatases or target directed enzymes.

Prodrug: Undesirable Properties Physical properties: Poor aqueous layer Low lipophilicity Chemical instability Pharmacokinetic properties: Poor distribution across biological membranes Good substrate for first pass metabolism Rapid adsorption / excretion when long-term effect

desired.

Prodrug: Steps Of Prodrug Design

Identification of drug delivery problem Identification of desired physicochemical properties Selection of transport moiety which will Give prodrug desired transport properties Be readilly cleaved in the desired biologocal

compartment.

Prodrug: Example Of Some Prodrug

Fig: Enalapril, which is bioactivated by esterase to active enalaprilat.

Prodrug: Example Of Some Prodrug

Fig: Valaciclovin, which is bioactivated by esterase to active aciclovir.

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