This document provides an overview of drug metabolism and biotransformation. It defines biotransformation as the biochemical alteration of drugs or xenobiotics by enzymes. The liver is identified as the major site of biotransformation. Drug metabolism occurs in two phases - phase I involves reactions like oxidation, reduction and hydrolysis. Phase II involves conjugating reactions. Factors like enzyme induction and inhibition can influence the extent of drug metabolism. Cytochrome P450 enzymes and phase I and II enzymes involved in biotransformation are also discussed.
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
Metabolic Changes of Drugs and Related Organic Compounds describes the human metabolic processes of various functional groups found in therapeutic agents.
The importance of a chapter on metabolism lies in the fact that drug interactions are based on these processes.
For pharmacists, it is necessary for them to understand why certain drugs are contraindicated with other drugs.
This chapter attempts to describe the various phases of drug metabolism, the sites where these biotransformation will occur, the role of specific enzymes, metabolism of specific functional groups, and several examples of the metabolism of currently used therapeutic agents.
Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism.
Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism
biotransformation of drug
Biotransformation/Xenobiotic metabolism/ drug metabolism/detoxification.
-Xenobiotics: a wide variety of foreign compounds to which humans get exposed in day to day life.
-It includes unknown compounds, drugs, environmental pollutants, toxins.
-Many xenobiotics can evoke biological responses.
DEFINITION
The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and there by may activate or deactivate the drug is called biotransformation.
Why Biotransformation is necessary?:
To easily eliminate the drug
To terminate drug action by inactivating it
Consequences of Biotransformation
Active to Inactive:
Phenobarbitone---- Hydroxyphenobarbitone
Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
Sites of biotransformation
In the body: Liver, small and large intestines, lungs, skin, kidney, nasal mucosa & brain.
Liver is considered “metabolite clearing house” for both endogenous substances and xenobiotics.
Intestines are considered “initial site of drug metabolism”.
FIRST PASS METABOLISM:
First pass metabolism or presystemic
metabolism or ‘first pass effect’
After oral administeration many drugs are absorbed from the small intestine - transported first via portal system to the liver, where they undergo extensive metabolism before reaching systemic circulation.
fundamental concepts in drug biotransformation
Lipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances.
Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.
Enzymes catalyzing phase I biotransformation reactions
Enzymes catalyzing phase I biotransformation reactions include:
cytochrome P-450
aldehyde and alcohol dehydrogenase
deaminases
esterases
amidases
epoxide hydratases
Addition of water
Cleavage of R-O or R-N bond accompanied by addition of H2O
CYTOCHROME P450
The cytochrome P-450 families are referred to using an arabic numeral, e.g., CYP1, CYP2, etc.
Each family has a number of subfamilies denoted by an upper case letter, e.g., CYP2A, CYP2B, etc.
The individual enzymes within each subfamily are denoted by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Biotransformation of antibiotics, steroids and their applicationssuraj begoor
Biotransformation is a process in which a drug molecule gets converted from one form to another form.
It may be more or less active than the parent drug molecule.
In the body there are process like absorption, distribution, metabolism and excretion which is also called as ADME.
The Biotransformation of the drug usually takes place in the metabolism phase.
Biotransformation of the drug is a very important process which helps eliminate the drug molecules from getting stored in the body after its intended use is over.
The biotransformation of the drug takes place in the liver ( majority of the times it has been seen) other organs also play a role in biotransformation like lungs , kidney etc
biotransformation is helpful to maintain the healthy balance in the body as the toxins are eliminated in a fairly good amount.
Glucouronic acid pathway and biotransformationberuk2010
This slide talks about glucouronic acid pathway, biotransformation and its role in detoxification's in our body and it also discusses the enzymes involved in this pathway.
A study of effect of Saccharomyces cerevisiae on three substrates namely vanillin, orange peel oil and clove oil. The method uses HPTLC for analysis of biotransformation products.
Advantages of microbial biotransformation of bioactive compounds & microbial ...Radwa Ahmed
advantages of the use of microbial biotransformation in the field of natural products.
The microbial models for mammalian drug metabolism and applications in drug studies
drug metabolism, phase I metabolism, biotransformation, Xenobiotics- substances foreign to body
Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted.
Advantages of metabolism
Termination of drug action
↓ toxicity
Reduced lipophilicity.
Renal / biliary excretion ↑
↑ water solubility
↑ polarity
↑ excretion
Loss of phsiological activity
Active drug → more active drug
Non Active drug → active drug
Active drug → inactive drug
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
BIOTRANSFORMATION REACTIONS - 2 TYPES
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
Metabolite is usually inactive
Depending upon nature and localisation of enzymes which catalyse reaction –
Microsomal enzymes
Non- Microsomal enzymes
Oxidation of alcohol
ethanol→ acetaldehyde → acetic acid →TCA cycle → CO₂
Eg.
chloral hydrate → trichloroacetic acid
mefenamic acid → hydroxy methyl derivative
ALIPHATIC HYDROXYLATION
Hydroxyl group added to drug
RCH2CH3 O RCHOHCH3
Salicylic acid to Gentisic acid
Ibuprofen
Tolbutamide, Chlorpropamide,
pharmacokinetics- action of body on the drug. includes absorption, dissolution, metabolism and excretion of drug. In this presentation metabolism and excretion of the drug are covered . Includes conversion of lipophilic / non-water soluble compounds into easily removable compounds by the action of hepatic enzymes which can be microsomal or non-microsomal . Excretion is further removal or elimination of compounds or agents from the body. Drug elimination is the sum of the processes of removing an administered drug from the body. In the pharmacokinetic ADME scheme (absorption, distribution, metabolism, and excretion), it is frequently considered to encompass both metabolism and excretion. Hydrophobic drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures. Introduction
Most drugs are xenobiotics, ie, chemical substances not naturally produced by the body. Xenobiotics undergo various body processes for detoxification, thus reducing their toxicity and allowing them to be readily available for excretion. These processes allow for the chemical modification of drugs into their metabolites and are known as drug metabolism or metabolic biotransformation.
These metabolites are the byproducts of drug metabolism and can be characterized by active, inactive, and toxic metabolites. Active metabolites are biochemically active compounds with therapeutic effects, whereas inactive metabolites are biochemically inactive compounds with neither a therapeutic nor toxic effect. Toxic metabolites are biochemically active compounds similar to active metabolites but have various harmful effects.
Drug metabolism occurs at a specific location in the body, resulting in a low concentration of active metabolites in the systemic circulation. This phenomenon is called first-pass metabolism because it limits drug bioavailability. First-pass metabolism primarily occurs in the liver; however, metabolizing enzymes can be found throughout the body.
Understanding these alterations in chemical activity is crucial in utilizing the optimal pharmacological intervention for any patient. This is a topic of interest to any provider who routinely treats patients with medications. The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down or not is covered.pharmacokinetic
Normally, lipophilic xenobiotics that enter an animal’s body are rapidly detoxified. Detoxification
can be divided into phase I (primary) and phase II (secondary) processes (Figure 8.1). Phase I reactions consist of oxidation, hydrolysis, and reduction. The phase I metabolites are sometimes polar
enough to be excreted but are usually further converted by phase II reactions. In phase II reactions,
the polar products are conjugated with a variety of endogenous compounds such as sugars, sulfate,
phosphate, amino acids, or glutathione and subsequently excreted. Phase I reactions are usually
responsible for decreasing biological activity of a toxicant, and, therefore, the enzymes involved
are rate limiting with respect to toxicity. The most important function of biotransformation is to
decrease the lipophilicity of xenobiotics so that ultimately they can be excreted. In insects, the
major tissues involved in the metabolism of xenobiotics are the midgut, fat body, and Malpighian
tubules.
metabolism of xenobiotis, drugs, medicine, carcinogen generation by enzymes like cyt p450 mono oxigenases, prostaglandin synthase ect. alcohol metabolism, toxin metabolism, definition of genobiotics, biotransformation, detoxification. effects on health
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
Polymorphism affecting Drug Metabolism.pptxAnagha R Anil
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.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Couples presenting to the infertility clinic- Do they really have infertility...
Vijay biotransformation
1. DR.VIJAYA KRISHNA
Post graduate student
Department of Pharmacology
GANDHI MEDICAL COLLEGE
Hyderabad, AP.
01 AUG 2012
2. PLAN OF PRESENTATION
• INTRODUCTION
• DEFINITION
• SITES OF BIOTRANSFORMATION
• PHASES OF DRUG METABOLISM
• PHASE-I REACTIONS
• PHASE-II REACTIONS
• ENZYME INDUCTION
• ENZYME INHIBITION
• FACTORS AFFECTING DRUG
METABOLISM
• REFERENCES
3. INTRODUCTION
• Biotransformation/Xenobiotic metabolism/
drug metabolism/detoxification.
• Xenobiotics: a wide variety of foreign
compounds to which humans get exposed
in day to day life.
• It includes unknown
compounds, drugs, environmental
pollutants, toxins.
• Many xenobiotics can evoke bilogical
responses.
4. DEFINITION
• The biochemical alteration of drug or
xenobiotic in the presence of various enzymes
that acts as a catalyst which themselves not
consumed in the reaction and there by may
activate or deactivate the drug is called
biotransformation.
5. Why Biotransformation is necessary?:
• To easily eliminate the drug
• To terminate drug action by inactivating it
By changing its physicochemical properties
from: Active /inactive Inactive /active
Lipophilic Hydrophilic
Unionised Ionised
Nonpolar Polar
Plasma protein Free
bound
6. Consequences of Biotransformation
• Active to Inactive:
Phenobarbitone----
Hydroxyphenobarbitone
• Inactive (prodrug) to Active :
L-Dopa ---- Dopamine
Parathion -- Paraoxon
Talampicillin -- Ampicillin
7. • Active to equally active:
Diazepam -- Oxazepam
Amitriptyline -- Nortriptyline
Imipramine -- Des-imipramine
Codeine -- Morphine
8. Sites of biotransformation
• In the body: Liver, small and large
intestines, lungs, skin, kidney, nasal mucosa &
brain.
• Liver is considered “metabolite clearing house”
for both endogenous substances and xenobiotics.
• Intestines are considered “initial site of drug
metabolism”.
9. FIRST PASS METABOLISM:
• First pass metabolism or presystemic
metabolism or ‘first pass effect’
• After oral administeration many drugs are
absorbed from the small intestine -
transported first via portal system to the
liver, where they undergo extensive
metabolism before reaching systemic
circulation.
26
10. • First pass effect :Liver-90%, Git-9% and Portal
circulation-1%
• Partially metabolised drugs -
nitroglycerine,propranolol,salbutamol- high
oral dose is required.
• Complete first pass metabolism -
isoprenaline, hydrocortisone, insulin.
• Liver diease- increased bioavailability of drugs.
12. With in the cell: Endoplasmic reticulum.
smooth ER microsomal reactions
rough ER protein synthesis
13. PHASES OF DRUG METABOLISM
PHASE I REACTION PHASE II REACTION
1.Degradative reaction 1.Synthetic reaction
2.Introduction of functional group 2.Conjugates phase 1 metabolite
( -OH, -NH2,-SH,-O -,-COOH) with glucuronic acid,sulfate,acetyl,
methyl groups.
3.Mainly microsomal 3.Microsomal, Mitochondrial &
Cytoplasmic
4.Metabolites formed may be 4.Metabolites formed are usually
smaller, polar/non-polar larger,polar,water soluble & Inactive
Active/Inactive
14. DRUG METABOLIZING ENZYMES
ENZYMES REACTIONS
PHASE 1 “OXYGENASES”
CYP 450 C & O OXIDATION,DEALKYLATION,
FMO N, S & P OXIDATION
EPOXIDE HYDROLASES HYDROLYSIS OF EPOXIDES
PHASE 2 “TRANSFERASES”
SULFOTRANSFERASES(SULT) ADDITION OF SULFATE
UDP-GLUCURONOSYLTRANSFERASES(UGT) ADDITION OF GLUCURONIC ACID
GLUTATHIONE-S-TRANSFERASES(GST) ADDITION OF GLUTATHIONE
N-ACETYL TRANSFERASES(NAT) ADDITION OF ACETYL GROUP
METHYLTRANSFERASES(MT) ADDITION OF METHYL GROUP
OTHER ENZYMES
ALCOHOL DEHYDROGENASES REDUCTION OF ALCOHOLS
ALDEHYDE DEHYDROGENASES REDUCTION OF ALDEHYDES
NADPH-QUINONE OXIDOREDUCTASE(NQO) REDUCTION OF QUINONES
15. MICROSOMAL ENZYMES NON-MICROSOMAL
ENZYMES
1.Smooth endoplasmic reticulum 1.Cytoplasm, mitochondria of
of cells of liver,git,kidney,lungs & hepatic & other tissues(plasma).
skin.
2.Non-specific,inducible. 2.Non-inducible.
3.PHASE-I: most oxidation & 3.PHASE-I: most hydrolysis,
reduction, some hydrolysis. some oxidation & reduction.
4.PHASE-II: only glucuronide 4.PHASE-II: all except
conjugation. glucuronide conjugation.
5.Mainly MFO’s like CYP 450, 5. Include MAO, esterases,
FMO’s, EH, UGT amidases ,transferases ,
conjugases.
16. CYTOCHROME P450
In the Oxido-reductase process 2 microsomal
enzymes play a key role
Flavo proteins ,NADPH –cyt p-450
oxido-reductase
Haemoprotein,cyt p-450 serves as terminal
oxidase
• P450 heme reduction is rate limiting step
17. • Microsomal drug oxidations require p450,p450
reductase, NADPH ,O2
• Very low substrate specificity.High lipid solubility
is the only common structural feature of most of
substrates.
• P450 isoforms in liver –cyt1A2 ,2A6 ,2B6
,2C8, 2C9, 2C18, 2C19, 2D6, 2E1,3A4,3A5
18. Of these isoforms 3A4/5 carry out
biotransformation of about 50% of drugs.
P450 enzymes classified into families denoted by
numbers -1,2,3 and sub families by A,B,C & D
basis of AA sequence and c-DNA . Another
number indicates –specific isoenzymes.
19. NADP+ Drug
CYP CYP Fe+3
e-
R-Ase Drug Drug OH
NADPH
CO CYP Fe+3
CO
CYP-Fe+2 CYP Fe+2 Drug OH
Drug hu
Drug
e-
O2
CYP Fe+2 H2O
O2 Drug
2H+
Electron flow in microsomal drug oxidizing system
26. Flavin Monooxygenases
• Also known as zeigler’s enzyme. Neither inducible nor
inhibited.
• six families-FMOs(FMO3 being the most abundant in
liver.)
• FMO3 is able to metabolize nicotine,cimetidine and
ranitidine,clozapine and itopride.
• A genetic deficiency in this enzyme causes the fish-odor
syndrome due to a lack of metabolism of
trimethylamine N-oxide (TMAO) to trimethylamine
(TMA).
31. Non-Enzymatic Biotransformation
• Skeletal muscle relaxants like ATRACURIUM are
metabolised in the plasma spontaneously
through molecular rearrangement without
involvement of any enzyme action.
32. ENZYME INDUCTION
Xenobiotics can influence the extent of drug metabolism
1.by activating transcription
2.by inducing expression of genes
34. Aryl hydrocarbon Receptor(AHR):
• Induces CYP1A1,1A2,1B1--> activates procarcinogens
• Omeprazole is ligand.
• AHR is a member of super family of transcription
factors (PERIOD,SIMPLEMINDED,HIF).
• AHR has regulatory role in the development of
mammalian CNS – modulating the response to
chemical & oxidative stress.
35. Pregnane X Receptor:
• Structurally similar to steroid hormone receptors.
• Induces CYP3A4 ,Drug Transporters, SULT’s, UGT’s
• LIGANDS: Pregnanolone-16-carbonitrile, Rifampin,
Troleandomycin, Nifidipine, Mevastatin,
troglitazone, Ritonavir, paclitaxel, hyperforin.
• Basis for contraceptive failure.
36. Constitutive Androstane Receptor(CAR):
• Can activate genes even in absence of their ligands.
• LIGANDS: Pesticide 1,4-bisbenzene,
5-pregnane-3,20-dione.
• Induces CYP2B6, 2C9, 3A4, GST, UGT, SULT, Drug &
endobiotic transporters.
• Inverse agonists-androstanol, clotrimazole,meclizine
PXR & CAR exhibits species difference
Ex: 1.Rifampicin activates human PXR but not that of Rat.
2.Pregnanolone-16-carbonitrile- activates mouse,rat PXR.
3.Meclizine inhibits human CAR but activates mouse CAR.
37. Peroxisome Proliferator Activated Receptor
α(PPARα):
• Highly expressed in liver & kidney.
• LIGAND: 1.fibrates(gemfibrozil, fenofibrate),
2. hypoglycemic drugs(rosiglitazone, pioglitazone)
• Induces 1.enzymes- fatty acids(Arachidonic acid)
2.CYP4A - oxidation of FA & drugs with FA
side chain(leukotiene analogues)
• PPARα does not induce xenobiotic metabolism
39. ENZYME INHIBITION
• It is basis for several drug interactions. It is a rapid
process.
• Microsomal: 1.Reversible – cimetidine &
ketoconazole binds tightly to cyp450 heme iron and
inhibits metabolism of testosterone.
• Troleandomycin & Erythromycin--> CYP3A4-->
cyp3A4-metabolite complex.
• Proadifen(SKF-525-A)--> bind tightly to heme iron
and partially irreversibly inhibits enzyme.
40. 2. Irreversible(suicidal inhibitors)- intermediate
metabolite bind covalently with P450 apoprotien.
Ex: spironolactone, ethinyl estradiol, ritonavir
But Secobarbital inhibits CYP2B1 by binding to heme &
protein moieties.
Non-microsomal:
DRUG ENZYME INHIBITED
ALLOPURINOL XANTHINE OXIDASE
NSAIDS CYCLO-OXYGENASE
THEOPHYLLINE PHOSPHODIESTERASE
DISULFIRAM ALDEHYDE DEHYDROGENASE
42. • UGT are encoded by 19 genes(9genes on UGT1 locus-
chr.2 & 10genes on UGT2 locus-chr.4)
• UGT1- Glucuronidation of Bilirubin-rate limiting
step.
• UGT2 have greater specificity for endogenous
substances(steroids) glucurodination.
43. PHASE-II REACTIONS
SULFATION(cytosolic):
Sulfotransferase(SULT) conjugates sulfate- PAPS to
the hydroxyl groups & less frequently to aromatic
and aliphatic amine groups (acetaminophen,
hydroxycoumarins).
SULT has 13 isoforms.
SULT play an important role in normal human
homeostasis.
SULT2B1b –skin-cholesterol-cholesterol sulfate-
regulates keratinocyte differentiation & skin
development.
44. • SULT2A1-fetal adrenal gland -dehydroepiandrosterone
- DHEA sulfate-essential for placental Estrogen
biosynthesis during 2nd half of pregnancy.
• SULT1A3- highly selective for catecholeamines.
• SULT1E1-sulfates endogenous & exogenous steroids.
Ex:-Estrogen(17-estradiol)-estrogen sulfate.
• In humans significant fractions of circulating
catecholamines,estrogens,iodothryronines, DHEA are
exist in sulfate form.
45. PHASE-II REACTIONS
GLUTATHIONE CONJUGATION :
Glutathione(GSH) is a tripeptide of
glycine - glutamic acid - cysteine.
• GSH exists in cell as oxidized form(GS-SH) and
reduced form(GSH).
• GSH:GSSH ratio is critical in maintaining cellular
environment to be in reduced state.
• GSH + Electrophilic compound
GST otherwise react with –O,-N,-S atoms leading to cell damage
Electrophile-Glutathione
46. GLUTATHIONE-S-TRANSFERASE(GST):
• exists in 20 isoforms.
• Cytosolic GST isoforms -7classes - exogenous
drugs & xenobiotics (acetaminophen, ethacrynic
acid, bromobenzene)
• Microsomal GST isoforms-endogenous
leukotrienes & prostaglandins.
• GST play an important role in cellular
detoxification.
47. Its activity in cancerous tissue has been linked to
development of resistance to chemotherapeutic
agents.
Anticancer drug----> JNK &P38---->Apoptosis
- Resistance
GST over expression
In tumour cells
Inhibition of GST activity sensitises tumour cells to
anticancer drugs.
TLK199(GSH analogue) activated by plasma
esterase to TLK117(GST inhibitor) which potentiates
toxicity of anticancer drugs.
48. N-Acetylation(cytosol):
• Substrate- Aromatic amine groups & Hydrazine group
such as sulfonamides,isoniazid,clonazepam,
dapsone,etc.
• Co-substrate- acetyl coenzyme A
• Enzyme- N-Acetyl Transferase
NAT1 & NAT2 – 25 Allelic variants are identified.
NAT2 mutation – slow & fast acetylation.
Field of pharmacogenetics has established by the
identification of “The characterisation of an
Acetylator phenotype.”
50. Amino acid conjugation(mitochondria):
Substrate: aspirin, benzoic acid, nicotinic acid,
deoxycholic acid
Co-substrate: Glycine (or) Glutamine
Enzyme: acyl coenzyme A-glycinetransferase
Riboside & Riboside phosphates:
Many purines & pyrimidines form their active
metabolites by forming ribonucleosides and
ribonucleotides.
Purines and pyrimidines are used as antimetabolites in
cancer chemotherapy.
52. FACTORS AFFECTING DRUG METABOLISM
• Sex: male rats metabolise the drugs much faster
than female rats and prepubertal male rats.
male rats sleep for a shorter duration than
female rats after receiving hexobarbital.
In Humans similar sex differences exist for
propranolol, ethanol, estrogens, salicylates.
53. FACTORS AFFECTING DRUG METABOLISM
• Species: Rabbits metabolise Atropine faster than
man as they have high Atropine esterase activity
in the liver and plasma.
• Race: Chinese- high alcohol dehydrogenase
activity & low Aldehyde dehydrogenase activity-
high plasma aldehyde conc.- headache,
palpitation after consuming alcohol.
54. • Diet and environment:
Low carbohydrate-high protein diet-
metabolism.
High carbohydrate-low protien diet-
metabolism.
Starvation – enzyme inhibition.
Charcoal- broiled foods & cruciferous
vegetables induce CYP1A.
Grapefruit juice inhibit CYP3A.
Cigarette smokers metabolise some drugs
more rapidly than non-smokers
55. • Genetic polymorphism: Autosomal recessive traits.
PHASE-I: CYP2D6
DRUG PHENOTYPE EFFECT
debrisoquin PM orthostatic
hypotension
codeine PM dec. analgesic effect.
UM inc. respiratory
depression
tramadol PM inc. seizure risk
nortriptyline PM inc. ADR
UM dec. therapeutic
effect.
56. • PHASE-I: CYP2C19
DRUG PHENOTYPE EFFECT
amitriptyline PM dec. clearance. inc.
ADR
citalopram PM inc. GIT side effects
omeprazole EM inc. therapeutic effect
tamoxifen EM inc. endoxifen. inc.
efficacy. reduces risk of
relapse.
tamoxifen PM dec. endoxifen- dec.
(cyp2d6) therapeutic efficacy.
chlorproguanil EM inc. therapeutic
efficacy.
57. • PHASE-I: CYP2C9
DRUG PHENOTYPE EFFECT
CELECOXIB, PM INC. ADR
DICLOFENAC
WARFARIN PM INC. BLEEDING
RISK
TOLBUTAMIDE PM CARDIOTOXICITY
PHENYTOIN PM NYSTAGMUS,
DIPLOPIA, ATAXIA.