Genetic polymorphisms can profoundly influence drug metabolism, impacting how medications are processed in the body. Variations in genes encoding drug-metabolizing enzymes, like cytochrome P450 (CYP) enzymes, can lead to differences in drug efficacy and safety among individuals. This presentation provides a concise overview of how polymorphisms affect drug metabolism.
1. Introduction
2. Phases of metabolism
3. Phase-I Metabolism
4. Cytochrome P family
5. Phase –II Metabolism
6. First pass metabolism
7. Ante Drugs
8. Microsomal Enzymes induction
Role of metabolism in drug discovery
Introduction to drug metabolism case studies for its impacts on drug discover...SAPA-GP
2014/10/02 SAPA-GP Webinar:
Introduction to drug metabolism case studies for its impacts on drug discovery and development
Zhoupeng Zhang
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
Merck Research Laboratories
Sino-American Pharmaceutical Professionals Association (SAPA)
– A lecture for Medicinal Chemists
(October 2, 2014)
Polymorphism affecting drug metabolismDeepak Kumar
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. Variations in genes encoding drug-metabolizing enzymes like CYP450 isoforms can result in poor, intermediate, extensive, or ultra-rapid metabolizer phenotypes. This impacts how effectively an individual metabolizes and eliminates drugs from the body. The effects of inhibitors and inducers on drug metabolism also differ depending on a person's metabolizer phenotype. Understanding these genetic factors is important for predicting drug responses and interactions between a drug and other substances in an individual.
Cytochrome P450 enzymes are a superfamily of enzymes located in the endoplasmic reticulum of hepatic cells that catalyze oxidative reactions in phase 1 of drug metabolism. They require molecular oxygen and NADPH to convert non-polar compounds to more polar metabolites that can be eliminated. There are several isoforms of P450 enzymes that metabolize different drugs and have specific substrates, inhibitors, and inducers. The metabolism of many drugs can be increased or decreased through induction or inhibition of the P450 isoforms, resulting in unexpected changes to drug concentrations and effects.
Polymorphisms in genes encoding drug-metabolizing enzymes can affect individual responses to medications. Genetic variations produce different alleles of genes like CYP2C9, CYP2C19 and CYP2D6, which code for cytochrome P450 enzymes that metabolize many drugs in the liver. These polymorphisms can cause decreased, increased, or absent enzyme expression and activity, leading to subgroups that differ in their ability to metabolize drugs. For example, CYP2C19 polymorphisms are associated with longer half-lives of diazepam, while CYP2C9 variants increase bleeding risk when taking the blood thinner warfarin due to reduced metabolism. Understanding these pharmacogenomic differences can
The document provides an overview of drug metabolism. It discusses that drug metabolism is important as it converts lipophilic drugs to hydrophilic metabolites that can be readily excreted. The key sites of drug metabolism are the liver, GI tract, lungs and kidneys. Metabolism occurs via phase I and phase II reactions and can activate or deactivate drugs. Factors like enzymes, diet, disease and genetics influence an individual's metabolism. Understanding metabolism is important for drug efficacy, toxicity and interactions.
The document provides an overview of drug metabolism. It discusses that drug metabolism is important as it converts lipophilic drugs to hydrophilic metabolites that can be readily excreted. The key sites of drug metabolism are the liver, GI tract, lungs and kidneys. Metabolism occurs via phase I and phase II reactions and can activate or deactivate drugs. Factors like enzymes, diet and disease can influence a drug's metabolism. Understanding metabolism is important for predicting drug interactions and toxicity.
1) Biotransformation, or metabolism, involves the chemical alteration of drugs in the body by enzymes to make them more water soluble and easier to eliminate. This occurs mainly in the liver.
2) Phase I metabolism involves oxidation, reduction, and hydrolysis reactions using cytochrome P450 enzymes to introduce functional groups. Phase II metabolism involves conjugation reactions like glucuronidation and sulfation to further increase water solubility.
3) Factors like age, sex, disease states, genetic variations, and drug-drug interactions can impact drug metabolism by inducing or inhibiting metabolizing enzymes. Understanding a drug's metabolism is important for efficacy, safety, and interactions.
1. Introduction
2. Phases of metabolism
3. Phase-I Metabolism
4. Cytochrome P family
5. Phase –II Metabolism
6. First pass metabolism
7. Ante Drugs
8. Microsomal Enzymes induction
Role of metabolism in drug discovery
Introduction to drug metabolism case studies for its impacts on drug discover...SAPA-GP
2014/10/02 SAPA-GP Webinar:
Introduction to drug metabolism case studies for its impacts on drug discovery and development
Zhoupeng Zhang
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
Merck Research Laboratories
Sino-American Pharmaceutical Professionals Association (SAPA)
– A lecture for Medicinal Chemists
(October 2, 2014)
Polymorphism affecting drug metabolismDeepak Kumar
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. Variations in genes encoding drug-metabolizing enzymes like CYP450 isoforms can result in poor, intermediate, extensive, or ultra-rapid metabolizer phenotypes. This impacts how effectively an individual metabolizes and eliminates drugs from the body. The effects of inhibitors and inducers on drug metabolism also differ depending on a person's metabolizer phenotype. Understanding these genetic factors is important for predicting drug responses and interactions between a drug and other substances in an individual.
Cytochrome P450 enzymes are a superfamily of enzymes located in the endoplasmic reticulum of hepatic cells that catalyze oxidative reactions in phase 1 of drug metabolism. They require molecular oxygen and NADPH to convert non-polar compounds to more polar metabolites that can be eliminated. There are several isoforms of P450 enzymes that metabolize different drugs and have specific substrates, inhibitors, and inducers. The metabolism of many drugs can be increased or decreased through induction or inhibition of the P450 isoforms, resulting in unexpected changes to drug concentrations and effects.
Polymorphisms in genes encoding drug-metabolizing enzymes can affect individual responses to medications. Genetic variations produce different alleles of genes like CYP2C9, CYP2C19 and CYP2D6, which code for cytochrome P450 enzymes that metabolize many drugs in the liver. These polymorphisms can cause decreased, increased, or absent enzyme expression and activity, leading to subgroups that differ in their ability to metabolize drugs. For example, CYP2C19 polymorphisms are associated with longer half-lives of diazepam, while CYP2C9 variants increase bleeding risk when taking the blood thinner warfarin due to reduced metabolism. Understanding these pharmacogenomic differences can
The document provides an overview of drug metabolism. It discusses that drug metabolism is important as it converts lipophilic drugs to hydrophilic metabolites that can be readily excreted. The key sites of drug metabolism are the liver, GI tract, lungs and kidneys. Metabolism occurs via phase I and phase II reactions and can activate or deactivate drugs. Factors like enzymes, diet, disease and genetics influence an individual's metabolism. Understanding metabolism is important for drug efficacy, toxicity and interactions.
The document provides an overview of drug metabolism. It discusses that drug metabolism is important as it converts lipophilic drugs to hydrophilic metabolites that can be readily excreted. The key sites of drug metabolism are the liver, GI tract, lungs and kidneys. Metabolism occurs via phase I and phase II reactions and can activate or deactivate drugs. Factors like enzymes, diet and disease can influence a drug's metabolism. Understanding metabolism is important for predicting drug interactions and toxicity.
1) Biotransformation, or metabolism, involves the chemical alteration of drugs in the body by enzymes to make them more water soluble and easier to eliminate. This occurs mainly in the liver.
2) Phase I metabolism involves oxidation, reduction, and hydrolysis reactions using cytochrome P450 enzymes to introduce functional groups. Phase II metabolism involves conjugation reactions like glucuronidation and sulfation to further increase water solubility.
3) Factors like age, sex, disease states, genetic variations, and drug-drug interactions can impact drug metabolism by inducing or inhibiting metabolizing enzymes. Understanding a drug's metabolism is important for efficacy, safety, and interactions.
Phenobarbital induces UGT1A1 enzyme.
Phenobarbital is known to induce various drug metabolizing enzymes including UGT1A1. By inducing UGT1A1, it increases the enzyme's activity and ability to conjugate and clear bilirubin, thus lowering bilirubin levels in patients with Crigler-Najjar syndrome type II who have some residual UGT1A1 activity.
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. The document discusses how single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes like the cytochrome P450 system can result in poor, intermediate, normal, extensive, or ultra-rapid metabolizers. This genetic variation impacts the metabolism of many drugs and can influence their effects as well as drug interactions. The cytochrome P450 2C19 enzyme, which is important in metabolizing diazepam, shows polymorphisms that lead to different drug responses and side effects between ethnic populations. Understanding these pharmacogenomic factors is important for optimizing drug therapy.
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. Variations in genes encoding drug metabolizing enzymes, like CYP450 isoforms and dihydropyrimidine dehydrogenase, have been shown to result in decreased, increased, or absent enzyme expression/activity. This can lead to inter-individual differences in drug effects, like a higher risk of toxicity from drugs metabolized by the affected enzymes. Single nucleotide polymorphisms in these genes have been linked to variability in drug dosing requirements, interactions, and treatment outcomes.
This document discusses drug metabolism and elimination. It begins by defining metabolism as the chemical alteration of drugs in the body, which is needed to make nonpolar compounds polar so they can be excreted. The major sites of drug metabolism are the liver, kidneys, intestines, lungs, and plasma. Drugs may be inactivated, converted to an active metabolite, or activated from an inactive prodrug through biotransformation. Biotransformation involves phase I (functionalization) and phase II (conjugation) reactions. The kinetics of drug elimination, including clearance, half-life, and order of elimination, are also covered. The document provides detailed information on the various enzyme systems, organ systems, and pathways involved in
Microsomal enzymes like cytochrome P450 and UDP glucoronosyl transferases are important for drug metabolism in the liver and other tissues. Cytochrome P450 enzymes catalyze oxidation, reduction, and other phase I reactions. UDP glucoronosyl transferases catalyze phase II conjugation reactions like glucoronidation. Drug metabolism can be induced or inhibited by other drugs and environmental factors, leading to potential drug-drug interactions. A better understanding of an individual's genetic polymorphisms and environmental factors can help optimize drug therapy and avoid adverse reactions.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
Chapter 4 Pharmacogenetics of drug pharmacokinetic profile.pptxGalataanAnuma
This document discusses the pharmacogenetics of drug metabolism. It describes how genetic variations in enzymes and transporters involved in the pharmacokinetic processes of drugs can affect drug concentrations. It focuses on the Phase I and Phase II drug metabolizing enzymes and transporters, providing details on polymorphisms in cytochrome P450 enzymes like CYP2D6, CYP2C19 and CYP2C9 that can impact drug metabolism and response. It also discusses the impact of variations in enzymes like TPMT and DPD on drugs metabolized by these pathways.
This document provides an overview of pharmacogenetics and discusses:
1. Pharmacogenetics is the study of how genetic factors influence individual responses to drugs. It considers both environmental and genetic factors that impact drug metabolism and effects.
2. Key concepts include how genetic polymorphisms affect drug metabolizing enzymes and transporters, leading to variability in drug efficacy and risk of adverse reactions between individuals.
3. The field has progressed from early discoveries of genetic disorders affecting drug response to now understanding the effects of common gene variants, with the goal of personalized medicine to optimize drug therapy for each patient.
The document discusses various aspects of drug metabolism including:
1. Drug metabolism can lead to termination of drug action, activation of prodrugs, bioactivation and toxication, carcinogenesis, and teratogenesis.
2. Phase I and Phase II metabolic pathways are discussed in detail along with the enzymes involved such as cytochrome P450 and factors affecting drug metabolism.
3. Specific drug examples are provided to illustrate different metabolic pathways and implications like the interaction between grapefruit juice and CYP3A4 inhibiting drugs.
The document discusses various aspects of drug metabolism including:
1. Drug metabolism can lead to termination of drug action, activation of prodrugs, bioactivation and toxication, carcinogenesis, and teratogenesis.
2. Phase I reactions include oxidation, reduction and hydrolysis which make drugs more polar and expose them to phase II metabolism. Phase II conjugates drugs to make them more water soluble.
3. Cytochrome P450 enzymes are major drug metabolizing enzymes with different isoforms having distinct substrate specificities. Factors like genetic variations, coadministered drugs and diet can impact drug metabolism.
This document discusses drug metabolism and its implications. It covers several key points:
1. Drugs can be metabolized to terminate their action, activate prodrugs, or form toxic/carcinogenic metabolites. Metabolism can also lead to teratogenesis.
2. Factors like age, genetics, and coadministered drugs can influence a drug's metabolism. Many drugs undergo first-pass metabolism in the liver after oral administration.
3. Drug metabolism occurs through phase I and phase II pathways. Phase I involves reactions like oxidation and hydrolysis. Phase II conjugates drugs with endogenous molecules like glucuronic acid.
4. Cytochrome P450 isoenzymes like
1. Drug metabolism is the process by which the body breaks down or alters drugs through specialized enzyme systems. It aims to make drugs more polar, water soluble, and less lipid soluble to promote excretion.
2. Drug metabolism occurs through two phases - phase 1 involves changes like oxidation, reduction, or hydrolysis. Phase 2 involves conjugating the drug or its metabolites to endogenous substances.
3. Factors that influence drug metabolism include age, diet, genetic variation, health, nutrition, gender, protein binding, species differences, substrate competition, and enzyme induction or inhibition. Cytochrome P450 and conjugating enzymes are involved in the metabolic processes.
This document provides information about biotransformation and elimination of drugs. It defines biotransformation as enzyme-catalyzed reactions that metabolize drugs within the body. The major sites of biotransformation are the liver, kidneys, lungs, intestine, adrenal cortex, placenta, and skin. Biotransformation can produce inactive, active, or toxic metabolites. It also describes first-pass metabolism in the liver and factors that influence it. The document outlines the three phases of biotransformation - phase I and II reactions catalyzed by drug-metabolizing enzymes, and phase III transport of metabolites. It discusses drug-metabolizing enzymes like CYPs and factors like induction and inhibition that affect their activity.
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Xenobiotics are foreign compounds that are metabolized in the body. There are two phases of xenobiotic metabolism: phase 1 involves reactions like hydroxylation that make the compound more polar, while phase 2 involves conjugating it with molecules like glucuronic acid to further increase polarity and allow excretion. Cytochrome P450 enzymes play a key role in phase 1 as they hydroxylate a wide variety of xenobiotics to make them more soluble. Understanding how the body metabolizes xenobiotics is important for fields like pharmacology, toxicology, and cancer research.
Metabolism,Excretion,prodrug,Therapeutic Drug monitoringSrinivasSree11
1. Metabolism and excretion are important processes that determine the duration and intensity of a drug's effects in the body. Metabolism involves chemical alteration of drugs through phase I and phase II reactions, while excretion removes drugs and metabolites from the body through renal, hepatic, pulmonary and other routes.
2. Factors like age, diet, diseases, genetic factors and simultaneous administration of other drugs can influence drug metabolism by inducing or inhibiting drug-metabolizing enzymes. Metabolism can convert drugs to active, inactive or less active forms.
3. Prodrugs are inactive forms administered to deliver the active drug selectively or improve pharmacokinetics. They are converted to active drugs through metabolic processes
Pharmacokinetics metabolism and excretionsumitmahato20
This document discusses the metabolism and excretion of drugs. It covers the following key points:
1. Drugs undergo biotransformation primarily in the liver through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions to make them more polar and excretable.
2. The metabolites can be inactive, active, or activate prodrugs. Enzyme inhibition and induction can impact drug metabolism.
3. Excretion occurs mainly through the kidneys and liver into urine and bile. Lungs, saliva, sweat and milk are minor excretion routes.
4. The plasma half-life determines the dosing frequency needed to maintain therapeutic drug levels. D
A brief presentation about the transport of drugs across the cell membrane including the many mechanisms and various transporters and a brief overview of the ABC and SLC superfamily of transporters.
Physiology and chemistry of skin and pigmentation, hairs, scalp, lips and nail, Cleansing cream, Lotions, Face powders, Face packs, Lipsticks, Bath products, soaps and baby product,
Preparation and standardization of the following : Tonic, Bleaches, Dentifrices and Mouth washes & Tooth Pastes, Cosmetics for Nails.
Phenobarbital induces UGT1A1 enzyme.
Phenobarbital is known to induce various drug metabolizing enzymes including UGT1A1. By inducing UGT1A1, it increases the enzyme's activity and ability to conjugate and clear bilirubin, thus lowering bilirubin levels in patients with Crigler-Najjar syndrome type II who have some residual UGT1A1 activity.
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. The document discusses how single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes like the cytochrome P450 system can result in poor, intermediate, normal, extensive, or ultra-rapid metabolizers. This genetic variation impacts the metabolism of many drugs and can influence their effects as well as drug interactions. The cytochrome P450 2C19 enzyme, which is important in metabolizing diazepam, shows polymorphisms that lead to different drug responses and side effects between ethnic populations. Understanding these pharmacogenomic factors is important for optimizing drug therapy.
Genetic polymorphisms can affect how individuals metabolize and respond to drugs. Variations in genes encoding drug metabolizing enzymes, like CYP450 isoforms and dihydropyrimidine dehydrogenase, have been shown to result in decreased, increased, or absent enzyme expression/activity. This can lead to inter-individual differences in drug effects, like a higher risk of toxicity from drugs metabolized by the affected enzymes. Single nucleotide polymorphisms in these genes have been linked to variability in drug dosing requirements, interactions, and treatment outcomes.
This document discusses drug metabolism and elimination. It begins by defining metabolism as the chemical alteration of drugs in the body, which is needed to make nonpolar compounds polar so they can be excreted. The major sites of drug metabolism are the liver, kidneys, intestines, lungs, and plasma. Drugs may be inactivated, converted to an active metabolite, or activated from an inactive prodrug through biotransformation. Biotransformation involves phase I (functionalization) and phase II (conjugation) reactions. The kinetics of drug elimination, including clearance, half-life, and order of elimination, are also covered. The document provides detailed information on the various enzyme systems, organ systems, and pathways involved in
Microsomal enzymes like cytochrome P450 and UDP glucoronosyl transferases are important for drug metabolism in the liver and other tissues. Cytochrome P450 enzymes catalyze oxidation, reduction, and other phase I reactions. UDP glucoronosyl transferases catalyze phase II conjugation reactions like glucoronidation. Drug metabolism can be induced or inhibited by other drugs and environmental factors, leading to potential drug-drug interactions. A better understanding of an individual's genetic polymorphisms and environmental factors can help optimize drug therapy and avoid adverse reactions.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
Chapter 4 Pharmacogenetics of drug pharmacokinetic profile.pptxGalataanAnuma
This document discusses the pharmacogenetics of drug metabolism. It describes how genetic variations in enzymes and transporters involved in the pharmacokinetic processes of drugs can affect drug concentrations. It focuses on the Phase I and Phase II drug metabolizing enzymes and transporters, providing details on polymorphisms in cytochrome P450 enzymes like CYP2D6, CYP2C19 and CYP2C9 that can impact drug metabolism and response. It also discusses the impact of variations in enzymes like TPMT and DPD on drugs metabolized by these pathways.
This document provides an overview of pharmacogenetics and discusses:
1. Pharmacogenetics is the study of how genetic factors influence individual responses to drugs. It considers both environmental and genetic factors that impact drug metabolism and effects.
2. Key concepts include how genetic polymorphisms affect drug metabolizing enzymes and transporters, leading to variability in drug efficacy and risk of adverse reactions between individuals.
3. The field has progressed from early discoveries of genetic disorders affecting drug response to now understanding the effects of common gene variants, with the goal of personalized medicine to optimize drug therapy for each patient.
The document discusses various aspects of drug metabolism including:
1. Drug metabolism can lead to termination of drug action, activation of prodrugs, bioactivation and toxication, carcinogenesis, and teratogenesis.
2. Phase I and Phase II metabolic pathways are discussed in detail along with the enzymes involved such as cytochrome P450 and factors affecting drug metabolism.
3. Specific drug examples are provided to illustrate different metabolic pathways and implications like the interaction between grapefruit juice and CYP3A4 inhibiting drugs.
The document discusses various aspects of drug metabolism including:
1. Drug metabolism can lead to termination of drug action, activation of prodrugs, bioactivation and toxication, carcinogenesis, and teratogenesis.
2. Phase I reactions include oxidation, reduction and hydrolysis which make drugs more polar and expose them to phase II metabolism. Phase II conjugates drugs to make them more water soluble.
3. Cytochrome P450 enzymes are major drug metabolizing enzymes with different isoforms having distinct substrate specificities. Factors like genetic variations, coadministered drugs and diet can impact drug metabolism.
This document discusses drug metabolism and its implications. It covers several key points:
1. Drugs can be metabolized to terminate their action, activate prodrugs, or form toxic/carcinogenic metabolites. Metabolism can also lead to teratogenesis.
2. Factors like age, genetics, and coadministered drugs can influence a drug's metabolism. Many drugs undergo first-pass metabolism in the liver after oral administration.
3. Drug metabolism occurs through phase I and phase II pathways. Phase I involves reactions like oxidation and hydrolysis. Phase II conjugates drugs with endogenous molecules like glucuronic acid.
4. Cytochrome P450 isoenzymes like
1. Drug metabolism is the process by which the body breaks down or alters drugs through specialized enzyme systems. It aims to make drugs more polar, water soluble, and less lipid soluble to promote excretion.
2. Drug metabolism occurs through two phases - phase 1 involves changes like oxidation, reduction, or hydrolysis. Phase 2 involves conjugating the drug or its metabolites to endogenous substances.
3. Factors that influence drug metabolism include age, diet, genetic variation, health, nutrition, gender, protein binding, species differences, substrate competition, and enzyme induction or inhibition. Cytochrome P450 and conjugating enzymes are involved in the metabolic processes.
This document provides information about biotransformation and elimination of drugs. It defines biotransformation as enzyme-catalyzed reactions that metabolize drugs within the body. The major sites of biotransformation are the liver, kidneys, lungs, intestine, adrenal cortex, placenta, and skin. Biotransformation can produce inactive, active, or toxic metabolites. It also describes first-pass metabolism in the liver and factors that influence it. The document outlines the three phases of biotransformation - phase I and II reactions catalyzed by drug-metabolizing enzymes, and phase III transport of metabolites. It discusses drug-metabolizing enzymes like CYPs and factors like induction and inhibition that affect their activity.
Genetic polymorphisms are variations in gene sequences that occur in at least 1% of the general population, resulting in multiple alleles or variants of a gene sequence.
The most commonly occurring form of genetic variability is the single nucleotide polymorphism (SNP, often called “snip”)
Xenobiotics are foreign compounds that are metabolized in the body. There are two phases of xenobiotic metabolism: phase 1 involves reactions like hydroxylation that make the compound more polar, while phase 2 involves conjugating it with molecules like glucuronic acid to further increase polarity and allow excretion. Cytochrome P450 enzymes play a key role in phase 1 as they hydroxylate a wide variety of xenobiotics to make them more soluble. Understanding how the body metabolizes xenobiotics is important for fields like pharmacology, toxicology, and cancer research.
Metabolism,Excretion,prodrug,Therapeutic Drug monitoringSrinivasSree11
1. Metabolism and excretion are important processes that determine the duration and intensity of a drug's effects in the body. Metabolism involves chemical alteration of drugs through phase I and phase II reactions, while excretion removes drugs and metabolites from the body through renal, hepatic, pulmonary and other routes.
2. Factors like age, diet, diseases, genetic factors and simultaneous administration of other drugs can influence drug metabolism by inducing or inhibiting drug-metabolizing enzymes. Metabolism can convert drugs to active, inactive or less active forms.
3. Prodrugs are inactive forms administered to deliver the active drug selectively or improve pharmacokinetics. They are converted to active drugs through metabolic processes
Pharmacokinetics metabolism and excretionsumitmahato20
This document discusses the metabolism and excretion of drugs. It covers the following key points:
1. Drugs undergo biotransformation primarily in the liver through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions to make them more polar and excretable.
2. The metabolites can be inactive, active, or activate prodrugs. Enzyme inhibition and induction can impact drug metabolism.
3. Excretion occurs mainly through the kidneys and liver into urine and bile. Lungs, saliva, sweat and milk are minor excretion routes.
4. The plasma half-life determines the dosing frequency needed to maintain therapeutic drug levels. D
A brief presentation about the transport of drugs across the cell membrane including the many mechanisms and various transporters and a brief overview of the ABC and SLC superfamily of transporters.
Similar a Polymorphism affecting Drug Metabolism.pptx (20)
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2. CONTENTS
Drug Metabolism
Types of Drug Metabolism
Polymorphism
Types of Polymorphism
How Polymorphism affects Drug Metabolism?
Research Article
Reference
3. DRUG METABOLISM
• Drug metabolism (biotransformation) is the processby which the bodybreaks down and transforms drugs
into different chemical forms.
MAJOR FUNCTIONS
1. Activation of Prodrugs
Enalapril
𝑚𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑠𝑒𝑑 𝑡𝑜 𝑎𝑐𝑡𝑖𝑣𝑒 𝑓𝑜𝑟𝑚
Enalaprilat
2. Inactivation of Drugs
Losartan
𝐶𝑦𝑡𝑜𝑐ℎ𝑟𝑜𝑚𝑒 𝑃450
E-3174
𝐺𝑙𝑢𝑐𝑢𝑟𝑜𝑛𝑖𝑑𝑎𝑡𝑖𝑜𝑛/𝑜𝑥𝑖𝑑𝑎𝑡𝑖𝑜𝑛
excretedout
3. Excretion of Drugs
Caffeine
𝐶𝑦𝑡𝑜𝑐ℎ𝑟𝑜𝑚𝑒 𝑃450 1𝐴2
Paraxanthine
4. Detoxification
Paracetamol
𝐶𝑌𝑃2𝐸1
N-acetyl-p-benzoquinoneimine (NAPQI) 𝑡𝑜𝑥𝑖𝑐
𝐺𝑙𝑢𝑡𝑎𝑡ℎ𝑖𝑜𝑛𝑒 𝑆−𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑎𝑠𝑒
excretedout
5. First-pass Metabolism
Ethinylestradiol
𝐶𝑌𝑃3𝐴4
Less potent metabolitewith controlled and sustained releaseof estrogen
4. TYPES OF DRUG METABOLISM
PHASE I
Hydroxylation
Oxidation
Dealkylation
Deamination
Reduction
PHASE II
1.Glucuronidation
1.Sulfation
1.Methylation
1.Acetylation
1.Conjugation with Glutathione
1.Conjugation with Amino Acids
PHASE III
ATP-binding cassette (ABC)
Solute carrier (SLC) transporters
5. Phase I Metabolism
• Phase I metabolism is the initial step in the biotransformation of drugs in the body.
• Involves a series of enzymatic reactions that aim to modify the chemical structure of these
substances, usually by introducing or exposing functional groups.
• The primary purpose of Phase I metabolism is to increase the water solubility of the
compounds, facilitating their elimination from the body.
PHASE I REACTIONS
Hydroxylation Addition of a hydroxyl group to the drug molecule.
Oxidation Introduction of oxygen into the drug molecule.
Dealkylation Removal of alkylgroups from the drug molecule.
Deamination Removal of amino groups from the drug molecule.
Reduction Addition of electrons to the drug molecule.
6. Phase I Metabolism
ENZYMES INVOLVED (“oxygenases”)
• Cytochrome P450 (CYP) Enzymes
CYP3A4
CYP2D6
CYP2C9
CYP1A2
CYP2E1
CYP2C19
• Flavin-Containing Monooxygenases(FMOs)
• Monoamine Oxidases (MAOs)
• Alcohol Dehydrogenase(ADH)
• AldehydeDehydrogenase(ALDH)
• Xanthine Oxidase
• Esterases
• Epoxide Hydrolases
CYP3A4 is the most abundant isoenzyme in
the human liver and accounts for about
50% of all CYP450 activity.
7. Phase I Metabolism
Cytochrome P450 (CYP) Enzymes
most prominent enzymesinvolvedin Phase I metabolism
Heme-containing monooxygenases(donate–OHgroup)
Found in liver, intestines, lungs,kidneys,and the brain.
Fe3+
CYP450
Drug +
Drug
Fe3+
CYP450
NADPH
Drug
Fe2+
CYP450 𝑶𝟐
+
Fe3+
𝑶𝟐
−
Drug
CYP450
NADPH
Fe3+
𝑶𝟐
𝟐−
Drug
CYP450
2H+
𝑯𝟐𝑶
Fe3+
CYP450
DRUG
METABOLITE +
8. Phase II Metabolism
• Drugs that already have -OH, -NH2, or COOH groups bypassesPhase I and enter Phase II directly to become
conjugated.
• Addition of hydrophilic groups to the original molecule,a toxic intermediate or a nontoxic metabolite
formed in phase I, that requiresfurther transformation to increase its polarity.
• The ultimate goal of phase II reactions is to form water-solubleproducts that can be excreted by the body.
PHASE II REACTIONS
Glucuronidation X + glucuronicacid → X-glucuronide(catalyzed by UGTs)
Sulfation X + sulfate→ X-sulfate(catalyzed by sulfotransferaseenzymes)
Acetylation X + acetyl-CoA→ X-acetate(catalyzed by acetyltransferaseenzymes)
Methylation X + S-adenosylmethionine→ X-methyl(catalyzed by methyltransferaseenzymes)
GlutathioneConjugation X + glutathione → X-SG (catalyzed by glutathioneS-transferaseenzymes)
Amino Acid Conjugation X + amino acid → X-amino acid (conjugation with glycine or taurine)
9. Phase II Metabolism
ENZYMES INVOLVED (“transferases”)
• Glucuronidation: UDP-glucuronosyltransferases(UGTs)(e.g.,UGT1A1)
• Sulfation: Sulfotransferase enzymes(e.g.,SULT1A1 )
• Acetylation: Acetyltransferase enzymes (e.g.,N-acetyltransferase)
• Methylation: Methyltransferase enzymes (e.g.,catechol-O-methyltransferase)
• Glutathione Conjugation: Glutathione S-transferase (GST) enzymes(e.g.,GSTP1 )
• Amino Acid Conjugation: Enzymesvary depending on the specific amino acid involved (e.g.,glycine
conjugation is catalyzed by glycine N-acyltransferase).
Glucuronidation, the most common phase II reaction.
10. Phase III Metabolism
• Phase III drug metabolism involvesthe transport of drug metabolites (formedduring Phase I and Phase II
metabolism) across cell membranes for eventual excretion.
• This step is crucial for the elimination of drugs and their metabolites from the body.
TRANSPORTER SUPERFAMILIES
ATP-binding Cassette (ABC) Transporters Solute Carrier (SLC) Transporters
Function
ABC transporters are involved in the active
transport of various substrates, including
drugs and their metabolites, across cell
membranes.
SLC transporters facilitate the passive or
facilitated transport of substances, including
drugs, across cell membranes.
Examples
P-glycoprotein (ABCB1), multidrug resistance-
associated proteins (MRPs), breast cancer
resistance protein (BCRP).
SLC22 family (organic cation transporters, OCTs;
organic anion transporters, OATs), SLC47 family
(multidrug and toxin extrusion proteins, MATEs).
Role in Drug Metabolism
These transporters contribute to the efflux of
drugs and metabolites from cells, impacting
their bioavailability and distribution.
SLC transporters are involved in the uptake of
drugs from the blood into cells, influencing
drug distribution and elimination.
11. POLYMORPHISM
• Polymorphism,as related to genomics, refers to the presence of two or more variant forms of a specific
DNA sequence that can occur among different individuals or populations.
• These variations can be observedin the form of single nucleotide changes, insertions, deletions,or
rearrangements in the DNA sequence.
• DNA polymorphismsare producedby changes in the nucleotide sequence or length. These result from:
(i) Variations in the fragment length pattern producedafter digesting DNA with restriction enzymes
(ii) Variations in the size of a DNA fragment after PCR amplification
(iii) Variations in the DNA sequenceitself.
12. Types of Polymorphism
• RFLP – restriction fragment length polymorphism
Eg: Debrisoquine – poor metabolisers of this drug have RFLP in
CYP2D6 gene (decreasedmetabolism )
• VNTR – variable number of tandem repeats
Eg : Codeine – poor metabolisers of this drug have VNTR in CYP2D6
gene (ultrafast metabolism metabolism )
• SSR – simple sequencerepeats or STR – simple tandem repeat, i.e.
microsatellites
Eg: Thiopurine – SSR cause decreased enzyme activity
• SNP – single nucleotide polymorphism
Eg: Warfarin – SNP in CYP2C9 gene cause variation in anticoagulant
action
13. Types of Polymorphism
POLYMORPHISM NATURE DETECTION METHOD RESULT
RFLP(Restriction
Fragment Length
Polymorphism)
Biallelicpolymorphismsresulting
from point mutations affecting a single
restriction enzyme recognition site
(E*).
Southern blot analysis using a
DNA probe or PCR amplification
of the specific region.
Two fragment sizes (largeor
small)dependingon the
presence or absence of the
polymorphic restriction
fragment site (*).
VNTR (Variable Number
TandemRepeat)
Multiallelicpolymorphisms with
changes in the restriction fragment
brought about by the insertion of a
variable number of repeat units at the
polymorphic site.
Southern analysis after
restriction enzyme digests.
More polymorphic DNA
fragments, increasing the
chances of detecting
heterozygous patterns.
SSR(Simple Sequence
Repeat)
Microsatellites with polymorphism
due to repeats of simple sequences,
e.g., (CA)n.
PCR amplification.
Fragments of variable size
based on the number of repeats.
SNP (SingleNucleotide
Polymorphism)
Singlebase changes.
DNA sequencingor other
methods.
Biallelicor multiallelic
polymorphisms,frequently
found throughout the genome,
offering effective discrimination
of alleles.
14. Polymorphism affecting Drug Metabolism
• Enzymes responsiblefor drug metabolism (mostlythe CYP450 group) are potentially affected by genetic
polymorphisms.
• Any clinical implications of changes in drug metabolism depend on
Whether the affected enzyme is crucial for the activation or elimination of the drug or its metabolites.
The importance of the affected pathway in the overallactivation or elimination of the drug.
Whether there is any overlappingsubstrate specificity of CYP450groups of enzymes.
15. Polymorphism affecting Drug Metabolism
• Scenario 1: Route 1 is the major pathway for drug
elimination and it is affected by a polymorphismthat
results in less active enzyme.
• Scenario 2: Routes 2 and 3 are the major pathways for
drug elimination and they are affected by
polymorphismsthat result in lessactive enzymes.
• Scenario 3: Route 1 is the minor pathway for drug
metabolism and it is affected by a polymorphismthat
results in a less active enzyme.
• Scenario 4: Route 1 is the minor pathway and route 3 is
the major pathway for drug elimination. Route 3
enzymesare affected by polymorphismsthat result in
poor metabolism.
16. Polymorphism affecting Drug Metabolism
• Poor Metabolizers:
reducedor absent activity of CYP450 enzymes.
As a result,the metabolismof drugs that rely on theseenzymesmay be significantly slower, leading to higher drug
concentrations in the body.
Poor metabolizersmay be at an increased risk of adverse effects from certain drugs.
• Normal Metabolizers:
Normal metabolizershave the typical or most common geneticvariants for CYP450 enzymes.
Their drug metabolismis considered to be within the normal range.
• Ultrafast Metabolizers:
increased activity of CYP450 enzymes.
enzymes are processed more rapidly, leading to lower drug concentrations
in the body.
• Intermediate Metabolizers:
CYP450 enzyme activityis betweennormal and poor metabolizers.
The metabolism of drugs not as slow as in poor metabolizers.
17. Polymorphism affecting Drug Metabolism
ULTRAFAST METABOLIZERS:
• Codeine is metabolizedby CYP2D6. Ultrafastmetabolizerswith
multiplecopies of active CYP2D6 genes may rapidly convert codeine
to its active form, morphine, resulting in higher and potentiallytoxic
levels.
INTERMEDIATE METABOLIZERS:
• Tamoxifen is metabolizedby CYP2D6 to its active form. Intermediatemetabolizerswith reduced CYP2D6 activitymay have
slower conversion to the active metabolite,potentiallyimpacting the efficacyof tamoxifenin breast cancer treatment.
POORMETABOLIZERS:
• Clopidogrel is a prodrug activatedby CYP2C19. Poor metabolizerswith reducedor absent CYP2C19 activitymay have impaired
activation of clopidogrel, leading to a decreasedantiplateleteffectand potentially an increased risk of cardiovascular events.
NORMALMETABOLIZERS:
• Warfarin, an anticoagulant, is metabolizedby multipleCYP450 enzymes, including CYP2C9. Normal metabolizersefficiently
process warfarin, and their stable metabolismis crucial for maintaining the desired anticoagulant effect.
18. Summary
• Genetic polymorphismsin drug-metabolizing enzymes,particularly those in the cytochrome P450 family,
can significantly impact therapeutic outcomes.
• Individuals with different drug metabolism genotypesmay respond variably to the same dose of a drug,
leading to diverseclinical effects.
• The high polymorphismin drug-metabolizing enzymesemphasizes the need for an individualizedapproach
to prescribing rather than relying solelyon evidence-basedguidelines.
• Clinical trials often incorporate genetic tests for variations in CYP450genes to screen participants,
acknowledging the importance of genetic factors in drug response.
• Transitioning from a one-size-fits-allapproach to personalizedmedicine considers genetic diversity and
enhances the precision of drug therapy.
• The goal is to optimize drug efficacy, minimize adverseeffects,and improveoverall patient outcomes
through a more individual-based approach to prescribing medications.
19. Article
• Frontiers in Pharmacology
• Impact Factor: 5.6
• Publishedon: 18 March 2022
Enzymes involved in the metabolismof SLE Regimens
• CytochromeP450 (CYP)
• Glutathione S-Transferase (GST)
• ArylamineN-Acetyltransferase (NAT)
• UDP-Glucuronosyltransferase (UGT)
• Thiopurine S-Methyltransferase (TPMT)
• NAD (P) H Quinone Dehydrogenase(NQO)
PharmacodynamicMechanisms Involved
• Fc Gamma Receptor (FCGR)
• Interferon Gamma (IFNG) and Interleukin (IL)
• Toll-likeReceptor (TLR), Toll/Interleukin-1Receptor
Domain-ContainingAdapter Protein (TIRAP), Tumor
Necrosis Factor (TNF), and B-cellActivating Factor (BAFF)
• Innate ImmunityActivator (INAVA/C1orf106)
• AutoimmuneRegulator(AIRE)
• TMEM 245 (C9orf5) (Transmembrane Protein - 245)
• Glucocorticoid Receptor (GR), Heat Shock Protein (HSP),
and TNF Receptor-AssociatedProtein (TRAP)
The review emphasizes the need for considering
genetic profilesin SLE treatment for more effectiveand
personalizedapproaches.
20. References
• Molecular Pharmacology from DNA to Drug Discovery;John Dickenson et al
• Molecular Diagnostics, Fundamentals, Methods & Clinical Application; Lela Buckingham
• The Pharmacological basis of Therapeutics; Goodman and Gilman’s
• Elsevier
• PubMed
• Science Direct
• DNA Polymorphism - an overview | ScienceDirect
• Genetic Polymorphismsand the Clinical Responseto Systemic Lupus Erythematosus Treatment Towards
PersonalizedMedicine | Article
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.
4. cysteine conjugate of NAPQI
5. Ethinylestradiol is typically administered orally, commonly as part of oral contraceptive pills.After ingestion, the drug is absorbed from the gastrointestinal tract and enters the portal circulation.
Ethinylestradiol is then transported to the liver via the hepatic portal vein. This is a crucial step in the first-pass metabolism.