This document discusses biotransformation of xenobiotics. It defines xenobiotics as foreign substances to the body that can come from natural or artificial sources. Biotransformation involves enzyme-catalyzed biochemical transformations that make lipophilic compounds more water soluble so they can be excreted. The main sites of biotransformation are the liver, kidneys, intestines, and other tissues. Biotransformation reactions are divided into Phase I and Phase II reactions. Phase I reactions use oxidative, reductive and hydrolytic enzymes to make compounds more polar. Phase II reactions use conjugating enzymes to further increase polarity for excretion. Factors like drug-metabolizing enzymes and induction/inhibition can impact bi
Nephrotoxicology - Toxic Responses of the Kidney Deepmalya Ghosh
Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.
The term neurotoxicity refers to damage to the brain or peripheral nervous system caused by exposure to natural or man-made toxic substances. These toxins can alter the activity of the nervous system in ways that can disrupt or kill nerves.
Nephrotoxicology - Toxic Responses of the Kidney Deepmalya Ghosh
Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.
The term neurotoxicity refers to damage to the brain or peripheral nervous system caused by exposure to natural or man-made toxic substances. These toxins can alter the activity of the nervous system in ways that can disrupt or kill nerves.
Toxicology is the branch of science that deals with nature, effects, and detection of poison. The degree to which a substance can harm an organism is called toxicity. The types of toxicity depending upon the time of exposure of the toxicant have been described.
Biotransformation of Xenobiotics (Drugs/toxicant Metabolism)Fateh Mohammad
This presentation is about the drug metabolism or dexotification of chemicals and drugs. This will help for those who are in pharmaceutical industry or studying toxicology
Toxicology is the branch of science that deals with nature, effects, and detection of poison. The degree to which a substance can harm an organism is called toxicity. The types of toxicity depending upon the time of exposure of the toxicant have been described.
Biotransformation of Xenobiotics (Drugs/toxicant Metabolism)Fateh Mohammad
This presentation is about the drug metabolism or dexotification of chemicals and drugs. This will help for those who are in pharmaceutical industry or studying toxicology
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
At the end of this e-learning session students will learn:
1. Definition of biotransformation/ Metabolism and different factor affecting metabolism
2. Discuss Phase I/ Non synthetic/functionalization reaction and Phase II/ Synthetic/ Conjugation reaction
3. Explain drug induction and drug inhibition
Reference:
Reference: • K D Tripathi. Essentials of Medical Pharmacology. Seventh Edition. Jaypee
Publication. Page no:23-29.
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
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
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
- 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
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
2. OVERVIEW
What are xenobiotics
What is biotransformation
Sites of biotransformation
Drug metabolising enzymes
Phase I reactions
Phase II reactions
Factors affecting biotransformation reaction
Role of biotransformation in new drug development
Conclusion
Dr. Jerin James 2
3. XENOBIOTICS
Xenobiotics are substances foreign to the body
Xenos – foreign , bios – life
Can be from:
Natural sources –e.g. plant products, alkaloids, poisons
Artificially manufactured – e.g.drugs, chemicals , pesticides
Dr. Jerin James 3
4. DEFINITION :BIOTRANSFORMATION
•Enzyme catalysed
•Biochemical transformation of drug
•Within living organism
•Lipid soluble drug/metabolite → water soluble form
•Excreted through the kidney
•Mainly Liver
•Also kidney,intestine,adrenal cortex,lungs,placenta,skin
Dr. Jerin James 4
7. OUTCOMES OF
BIOTRANSFORMATION
1. Formation of active metabolite from inactive/prodrug.,
Telampicillin → Ampicillin
2. Formation of inactive drug from pharmacologically active
drug.,
2. Phenobarbitone → hydroxyphenobarbitone
3. Formation of an active drug from an equally active drug.,
Diazepam → Oxazepam
4. Formation of toxic metabolites
5. Change in pharmacological action/new action .,
Iproniazid → Isoniazid
(antidepressant) (antitubercular)
Dr. Jerin James 7
8. PHASES OF BIOTRANSFORMATION
REACTIONS
Drug oxdn/redn/ congugtn prdt
hydrolysis
Dr. Jerin James 8
PHASE I PHASE II
Some drugs directly enter Phase II
metabolism
Following Phase I the
drug may be activated,
unchanged or
inactivated
Conjugated
drug is usually
inactive
DRUG
9. PHASE I REACTIONS
Degradative reactions
Drug is converted to a smaller polar/non polar metabolite
By introduction of a new functional group
Mainly microsomal reactions
Few are non-microsomal
Oxidation, Reduction , Hydrolysis
Metabolites formed may be active/inactive
Dr. Jerin James 9
10. PHASE II REACTIONS
=Synthetic reactions
= conjugation reactions
Makes molecule more polar
Reactions are catalysed by microsomal/
mitochondrial/cytoplasmic enzymes
Metabolite formed is polar, water soluble , inactive
Dr. Jerin James 10
11. FIRST PASS METABOLISM/
PRE-SYSTEMIC ELIMINATION/
FIRST PASS EFFECT
Metabolism of a drug
That occur before drug entering systemic circulation
Occur for drugs that are taken orally
Significant amount of drug is inactivated before reaching systemic
circulation
Certain amount of drug is absorbed as it passes through GIT wall and
portal circulation
↓d bioavailability of the drug
Diminished therapeutic effect
Imipramine,morphine,propranolol,buprenorphine,lignocaine,testostero
ne
Bypassed by parenteral administration of drug Dr. Jerin James 11
13. MICROSOMAL
ENZYMES
Smooth endoplasmic reticulum of liver mainly &
intestinal mucosa, lung and kidney , between the
phospholipid bilayer
Principal enzymes- Mixed function Oxidases(
MFO) or Cytochrome P-450
Most important pathway of drug metabolism
They are a superfamily of enzymes,all of which
contain an iron containing protein –Heme
Hemoproteins
Heme contains one atom of iron in hydrocarbon
cage, that functions to bind O2 in the CYP active site
Enzyme in reduced f give a product whose
absorption peak is at 450 cm-1
e.g. glucoronyl trsnsferase
Non specific action
Can be induced/activated
Can metabolise only lipid soluble drugs
Cytochrome P450 = CYPDr. Jerin James 13
14. LOCATION
OF CYP
Goodman & Gilman, The pharmacological basis of therapeutics, 13th ed ,page 88 Dr. Jerin
James 14
15. CYTOCHROME P
450
Classified into families designated by no.’s 1,2,3
Subfamilies designated by letters A,B,C,D
Amino acid sequence
cDNA cloning studies
• Another number is added to indicate specific
isoenzyme
eg CYP 2D6
Dr. Jerin James 15
16. CYTOCHROME P
450
Important CYPs for drug metabolism :
CYP 3A
CYP 2D
CYP 2C
• Exhibit genetic polymorphism
• Result in interindividual variation in drug response
Dr. Jerin James 16
17. CYP 3A 4 & CYP 3A5
• Substrates
oSteroids
oMacrolides
oCCB
oHormones
oAntihistamines
Induced by
oBarbiturates
oCarbamazepine
oPhenytoin
oRifampicin
Inhibitted by(‘zole’ drugs,mycin drugs,CCBs,antihistaminics)
oErythromycin ,Claruthromycin
oKetoconazole, Fluconazole
oVerapamil,Diltiazem
oRitonavir
oGrapefruit juice Dr. Jerin James 17
19. CYP 2C8 ,CYP 2C9
Substrates
oPhenytoin
owarfarin
Inducers
oBarbiturates
oRifampicin
Inhibitors
ofluconazole
Dr. Jerin James 19
20. CYP 2C 19
Substrate
oDiazepam
oProton pump inhibitors
oTCA
ophenytoin
Inducers
oBarbiturates
oPhenytoin
Inhibitors
oFluoxamine
oTiclopidine
ofluoxetine
Dr. Jerin James 20
21. NON-
MICROSOMAL
ENZYMES
Present in cytoplasm,
Mitochondria of hepatocytes & other tissues,
Plasma
eg. MAO, Esterases, Amidases, Transferases &
Conjugages
Catalyse Phase II reactions (except glucuronide
conjugation), certain oxidations, reductions &
hydrolytic reactions
Non- inducible
Can be inhibited
Shows genetic variations
eg pseudocholine esterase ,Acetyl transferase
Dr. Jerin James 21
22. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
Oxidation, Reduction, Hydrolysis
Makes molecule more susceptible to Phase II reactions
Involve addition/uncovering of a reactive group
This functional group can be acted upon by phase II/ conjugating
enzymes
Dr. Jerin James 22
24. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
N-O-S- dealkylation
N-dealkylation: removal of one alkyl group from amino nitrogen
eg. Morphine → normomorphine
Mephobarbitone → phenobarbitone
O-dealkylation : removal of one alkyl group from
eg. phenacetin → paracetamol
S-dealkylation: removal of one alkyl group from
eg. 6 methyl thiopurine → mercaptopurine
N- & S- oxidation:
Eg. Chlorpromazine → chlorpromazine sulfoxide
Dr. Jerin James 24
25. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
Deamination
eg.amphetamine → phenyl acetone derivative
Desulfurisation
eg.parathion → paraoxon
Dr. Jerin James 25
26. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
2. NON-MICROSOMAL OXIDATION (CYP Independent)
Mitochondrial oxidation
eg. epinephrine → VMA
Cytoplasmic oxidation
eg. alcohol → acetaldehyde → acetic acid
Plasma oxidative process
eg.histamine → imidazole acetic acid
Dr. Jerin James 26
27. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
CYP P 450 independent oxidation enzymes:
Flavin Mono Oxygenases(FMO)
Alcohol Dehydrogenase(ADH)
Aldehyde oxidase
Xanthine oxidase
Peroxidase
Prostaglandin synthase
myeloperoxidase
Dr. Jerin James 27
30. PHASE I REACTIONS/
NON-SYNTHETIC REACTIONS
HYDROLYSIS
Microsomal hydrolysis
Pethidine → pethidinic acid
Hepatic membrane bound esterase
Non microsomal hydrolysis
by estrases and amides
Procaine → PABA
Atropine → Tropic acid
Dr. Jerin James 30
31. PHASE II REACTIONS/
SYNTHETIC REACTIONS
MICROSOMAL CONJUGATION
GLUCORONIDE CONJUGATION
Parent drug/Phase I metabolite that contain phenolic, alcoholic, carboxylic, amino/mercapto
groups
Undergo conjugation reaction with UDP glucuronic acid
Catalysed by UDP glucoronyl transferase enzyme
→ drug-glucuronide conjugate, polar, readily excreted
→inactive products ,( except morphine glucuronide which is active)
Drug + UDPGA → Drug-glucuronide + UDP
Glucoronyl transferase
Eg. Morphine, paracetamol, aspirin
Dr. Jerin James 31
32. PHASE II REACTIONS/
SYNTHETIC REACTIONS
NON MICROSOMAL CONJUGATION
1. N-Acetylconjugation (cytosol)
N-acetyl transferase
Acetyl CoA – co factor
R-NH2 → R-NH.CO.CH3
N-acetyl transferase
Acetyl CoA
Isoniazid, PAS , Dapsone, Sulfonamides
Dr. Jerin James 32
33. PHASE II REACTIONS/
SYNTHETIC REACTIONS
2. Sulfate conjugation ( cytosol)
Sulfotransferases
3’phospho adenosine 5-Phospho sulfate(PAPS) – cofactor
Sulfate conjugates are highly polar →excreted in urine
eg. Aspirin, methyl dopa, paracetamol, corticosteroids
Dr. Jerin James 33
34. PHASE II REACTIONS/
SYNTHETIC REACTIONS
3. Amino acid conjugation (Mitochondria)
Coupling with glycine/glutamine
Glycine transferase
Acetyl CoA – cofactor
Eg. Aspirin , Benzoic acid, Nicotinic acid
Dr. Jerin James 34
36. PHASE II REACTIONS/
SYNTHETIC REACTIONS
5. Glutathione conjugation (cytoplasm/microsomes)
Glutathione –S-transferase enzyme
Eg. Epoxides, No2 group containing drugs
Dr. Jerin James 36
37. PHASE II REACTIONS/
SYNTHETIC REACTIONS
6. Ribosides & Riboside phosphates
Formation of ribonucleosides & ribonucleotides
by purines and antimetabolites used in cancer chemotherapy
Dr. Jerin James 37
38. NON ENZYMATIC BIOTRANSFORMATION
(HOFFMANN E4LIMINATION)
Metabolism in the plasma spontaneously
Molecular rearrangement
Without enzyme action
Eg. Atracurium
Dr. Jerin James 38
39. SOME PECULIARITIES IN
BIOTRANSFORMATION
Phase II reaction before phase I
Same drug can be metabolised by different drugs simultaneously
e.g. Amitryptiline metabolised by CYP 2D6, 2C9 AND 2C19
Same CYP can metabolise different drugs simultaneously
e.g. CYP3A4 can bind and metabolize diazepam and testosterone simultaneously
Dr. Jerin James 39
ISONIAZID
N-ACETYL
CONJUGATE
(phase II )
HYDROLYSIS
(Phase I )
40. FACTORS AFFECTING
BIOTRANSFORMATION
1. Physico chemical properties of the drug
Molecular size
Acidity/basicity
Pka
Lipophilicity
Interaction with drug metabolising enzymes
2. Chemical properties of the drug
Enzyme induction
Enzyme inhibition
Environmental chemicals
3. Biological factors – age ,sex, diet..
Dr. Jerin James 40
41. FACTORS AFFECTING
BIOTRANSFORMATION
Dr. Jerin James 41
Enzyme induction
Xenobiotics induce metabolism of its own (auto metabolism) or other drugs by
binding to nuclear receptor and activating expression of target genes by
transcription
Goodman & Gilman, The pharmacological basis of therapeutics, 13th ed ,page 88
Goodman & Gilmans , The pharmacological basis of therapeutics, 13th Ed p-
42. FACTORS AFFECTING
BIOTRANSFORMATION
Enzyme inducers induce CYPs ,increase metabolism of many other drugs , resulting
in therapeutic failure
Eg. Barbiturates, Carbamazepine, Glutethimide, Griseofulvin, Phenytoin
,Primidone, Rifabutin, Rifampicin etc
th
Dr. Jerin James 42
43. FACTORS AFFECTING
BIOTRANSFORMATION
Enzyme inhibition
Enzyme inhibitors decrease drug metabolising capacity of CYPs
Inhibitors compete for active site of CYPs – drug cannot bind
Result in increase in drug level – that lead to drug toxicity
The potency of the inhibitor is determined by lipophilicity and strength of bond
between inhibitor and active site of CYP
Eg. Amiodarone, Clarithromycin, Clotrimazole, Erythromycin, Ketoconazole,
Metronidazole, Chloroquine, Ritonavir, Grape fruit juice etc
Dr. Jerin James 43
44. FACTORS AFFECTING
BIOTRANSFORMATION
Genetic variation
Drugs can behave diffferntly in different individuals due to genetic variations
Eg. People lacking Pseudo-choline esterase due to genetic variation , prolonged
apnoea can occur when Succinyl choline is administered
Goodman & gilmans. The pharmacoliogicla basis of therapeutics, 13th Ed
Dr. Jerin James 44
45. ROLE OF BIOTRANSFORMATION IN DRUG
DEVELOPMENT PROCESS
Two key elements of new drug development, Efficacy and Safety are directly
related to drug biotransformation.
The capacity to metabolise xenobiotics has made development of drugs more
time consuming and costly ,partly due to
Species difference in expression of enzymes that metabolise drugs &
thereby limit the utility of animal models to predict drug effects in humans
Interindividual variations in the capacity of humans to metabolise drugs
Drug-drug interactions involving xenobiotic metabolising enzymes
Metabolic activation of chemicals to toxic and carcinogenic derivatives
Dr. Jerin James 45
46. ROLE OF BIOTRANSFORMATION IN DRUG
DEVELOPMENT PROCESS
COMPUTER BASED (IN SILICO)
SYSTEMS
1. COMPACT
2. Camitro
3. META
4. MetabolExpert
5. METEOR
IN-VITRO SYSTEMS
1. Human liver S9 fractions
2. Human liver microsomes
3. Huan liver cytosol fractions
4. Hep G2 cell line
5. BC2 cell line
Dr. Jerin James 46
47. ROLE OF BIOTRANSFORMATION IN DRUG
DEVELOPMENT PROCESS
Human liver S9 fractions
Most widely used In-Vitro system for metabolic screening in new drug
development
Contain both Phase I and Phase II metabolic enzymes
The microsomes component of the S9 fraction contain cytochrome P450 isoforms
(phase I metabolism) and other enzyme activities. The cytosolic portion contains
the major part of the activities of transferases(phase II metabolism).
Relatively inexpensive
Easy to use
Can be automated comprehensive and high quality data at reasonable expense for
drug discovery programs
Dr. Jerin James 47
48. CONCLUSION
Xenobiotics are any substances foreign to the body
Biotransformation aims to convert water insoluble drugs/substances to water
soluble form and is excreted via kidney/bile.
In phase I reaction, addition of functional group dramatically changes the biological
property of the xenobiotic
CYP 450 is the principal enzyme of phase I reactions
In phase II reaction, the phase I metabolite is conjugated to increase the water
solubility
Biotransformation can determine the efficacy and toxicity of a drug by controlling
its biological t ½
Dr. Jerin James 48
49. CONCLUSION
Different factors that influence xenobiotic metabolism
CYP inducers and inhibitors are the most important cause for drug-drug interactions
Prediction of metabolism and ADRs by knowledge of biotransformation with
modern in vitro and in silico methods are emerging as the most important part in
new drug development process
Dr. Jerin James 49
50. References
1. K.D. Tripathi, Essentials of medical pharmacology, 7th Ed
2. Goodmann &Gilmann, Pharmacological Basis of Therapeutics,13th Ed
3. H.P. Rang, M.M.Dale,J.M. Ritter,P.KMoore Pharmacology, 5th Ed
4. Sharma & Sharma
Dr. Jerin James 50