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
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.
Drug metabolism /certified fixed orthodontic courses by Indian dental academy Indian dental academy
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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.
Drug metabolism /certified fixed orthodontic courses by Indian dental academy Indian dental academy
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www.linkedin.com/in/dr-aboobecker-siddique-p-a-200783a0
pharmacokinetics 2
fate of a drug
biotransformation :
Chemical alteration of the drug in a living organism is called bio-transformation.
Lipid soluble →Water soluble
So that not reabsorbed in Kidney
Site-Mainly liver
Others-Kidney, lungs, plasma, gut mucosa & skin
metabolism
xenonbiotics
microsomal enzyme induction
excretion
kinetics of elimination
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
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.
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.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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
4. IMPLICATIONS FOR DRUG METABOLISM
1. Termination of drug action
2. Activation of prodrug
3. Bioactivation and toxication
4. Carcinogenesis
5. Tetratogenesis
5. Termination of Drug Action
tropic acid and tropine
atropine
propranolol → hydroxypropranolol
(active) (active)
6. Termination of Drug Action
Conversion of drug to active metabolite to active
metabolite to inactive metabolite
8. Inactive Terfenadine is Converted to its Active
Metabolite Fexofenadine
terfenadine
fexofenadine
activation of prodrug
9. Some Xenobiotics Are Metabolized to Carcinogenic Agents
• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminoflluorene
Metabolites of these agents interact with DNA
carcinogenesis
10. Small Amounts of Acetaminophen is Converted to the
Reactive Metabolite N-Acetylbenzoquinoneimine
Bioactivation of acetaminophen; under certain conditions, the electrophile N-
acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis.
bioactivation
11. Thalidomide is a Teratogen
– THALIDOMIDE: Fetal malformations in
humans, monkeys, and rats occur due to
metabolism of the parent compound to a
teratogen. This occurs very early in gestation.
teratogensis
13. Factors Affecting Drug Metabolism
• Age
• Diet
• Genetic Variation
• State of Health
• Gender
• Degree of Protein Binding
• Species Variation
• Substrate Competition
• Enzyme Induction
• Route of Drug Administration
14. Factors Affecting Drug Metabolism
• Route of drug administration
– Oral versus systemic administration
15. Many Drugs Undergo First Pass Metabolism
Upon Oral Administration
• Oral administration
• Drug travels from gut to portal vein to liver
• Vigorous metabolism occurs in the liver. Little drug
gets to the systemic circulation
• The wall of the small intestine also contributes to first
pass metabolism
21. Velocity Of Metabolism Of A Drug
0 10 20 30 40 50 60 70
0
10
20
30
40
50
60
70
80
[Drug] mM
Velocity
(ng/g
tissue/min)
D:summer1Kmx1.pzm
22. Velocity Of Metabolism Of A Drug
0 5 10 15 20 25 30 35 40 45 50 55 60
0
10
20
30
40
50
60
70
80
first order metabolism
zero order metabolism
[Drug] mM
Velocity
(ng/g
tissue/min)
Kmx2.pzm
23. First Order Metabolism
v = Vmax [C]
Km + [C]
When Km >>> [C],
then v = Vmax [C] ,
Km
and v α [C]
Metabolism of the drug is a first order process. A constant
fraction of the remaining drug is metabolized per unit time.
Most drugs are given at concentrations smaller than the Km
of the enzymes of their metabolism.
A drug may be given in doses that produce blood
concentrations less than the Km of the enyzme for the drug.
24. Velocity Of Metabolism Of A Drug
0 5 10 15 20 25 30 35 40 45 50 55 60
0
10
20
30
40
50
60
70
80
first order metabolism
zero order metabolism
[Drug] mM
Velocity
(ng/g
tissue/min)
Kmx2.pzm
25. Zero Order Metabolism
v = Vmax [C]
K m + [C]
When [C] >>> Km,
then v = Vmax [C] ,
[C]
and v = Vmax
Metabolism of the drug is a zero order process. A constant
amount of the remaining drug is metabolized per unit time.
Phenytoin undergoes zero order metabolism at the doses
given.
A drug may be given in doses that produce blood concentrations
greater than the Km of the enyzme for the drug.
26. Velocity Of Metabolism Of A Drug
0 5 10 15 20 25 30 35 40 45 50 55 60
0
10
20
30
40
50
60
70
80
first order metabolism
zero order metabolism
[Drug] mM
Velocity
(ng/g
tissue/min)
Kmx2.pzm
27. Velocity Of Metabolism Of Three Drugs
By The Same Enzyme
0 10 20 30 40 50 60 70 80 90
0
10
20
30
40
50
60
70
Drug A
Drug B
Drug C
[Drug] mM
Velocity
(ng/g
tissue/min
)
55. CYP3A4
• CYP3A4 is responsible for metabolism of 60%
of all drugs
• It comprises approximately 28% of hepatic
cytochrome P450
• Metabolizes terfenadine
• Ingestion of grapefruit juice reduces expression
of this enzyme
• Inhibited by some regularly used drugs
56. Some Drugs That Inhibit CYP3A4
• Macrolide antibiotics
– Erythromycin
– Clarithromycin
– Other such agents
• Antifungal agents
– Ketoconazole
– Itraconazole
– Other such agents
• HIV protease inhibitors
63. CYP3A4 And P-Glycoprotein
• P-Glycoprotein and CYP3A4 control oral bioavailability
of many drugs
• P-Glycoprotein and CYP3A4 share many substrates
and inhibitors
64. CYP2D6 is an Enzyme with Polymorphisms
• Approximately 70 nucleotide polymorphisms are
known
• Four phenotype subpopulations of metabolizers*
– Poor metabolizers (PM)
– Intermediate metabolizers (IM)
– Extensive metabolizers (EM)
– Ultrarapid metabolizers (UM)
• Variations according to racial background
• More than 65 commonly used drugs are
substrates
• Codeine is a well known substrate
* The Pharmacological Basis of Therapeutics
65. Codeine is a Substrate of CYP2D6
Consider the variation in codeine’s metabolism among
PM, IM, EM, UM individuals
-CH3
(methyl morphine)
66. CYP2C9
• Metabolizes some 16 commonly used drugs
• Warfarin and phenytoin are among the substrates
• Two allelic variants are known: metabolizes substrates
5% to 12% of the wild type enzyme
– Warfarin clearance is greatly reduced in individuals
possessing the allelic variants
• Dose adjustments are required for drugs in individuals
who have the mutant enzymes
67. CYP2C19
• S-mephenytoin is a substrate
– (4-hydroxylation at the phenyl ring)
• As much as eight allelic variants identified
– All are nonfunctional proteins
• Poor metabolizers of S-mephenytoin lack 4-hydroxylase
activity, but N-demethylation to nirvanol is an alternative
but slow metabolic pathway
– Dose adjustments must be made for poor
metabolizers of S-mephenytoin and for other drugs
that are substrates for this enzyme
68. CYP1A1
• Polycyclic hydrocarbons are among its
substrates
• Inducers include
– Polycyclic hydrocarbons such as 3,4,-benzopyrene,
3-methylcholanthrene, etc.
– Charcoal broiled foods (polycyclic hydrocarbons)
71. Nonmicrosomal Oxidations
Alcohol dehydrogenation is conducted by the enzyme
alcohol dehydrogenase (cytosolic)
Aldehyde dehydrogenation is conducted by the enzyme
aldehyde dehydrogenase (cytosol and mitochondria)
Xanthine oxidation is conducted by the cytosolic enzyme
xanthine oxidase.
Diamine oxidase (cytosolic) oxidizes histamine and
diamines such as cadaverine and putrescine.
Monoamine oxidation is conducted by mitochondrial
monoamine oxidase (norepinephrine, epinephrine,
dopamine and serotonin are endogenous substrates.
75. Alcohol Dehydrogenase
• A soluble enzyme, found almost exclusively in the
parenchymal cells of the liver
• Converts ethanol to acetaldehyde
• Converts methanol to formaldehyde
• Converts ethylene glycol to its respective aldehyde
metabolites
• Is inhibited by pyrazole
99. Uridine-5’-α-D-glucuronic Acid
The microsomal enzyme glucuronyl transferase conducts the
donation of glucuronic acid from the endogenously synthesized
UDPGA to various substrates to form glucuronide conjugates.
Examples of such substrates are morphine and acetaminophen.
100. UDP-α-D-Glucuronsyltransferase
• Is also called glucuronyl transferase
• A microsomal enzyme
• Substrates are called aglycones
• Conducts phase 2 metabolic reactions
• Products are called glucuronides
• Glucuronides formed
– RN-G; RO-G; RCOO-G; RS-G; RC-G
• Bilirubin is an endogenous substrate
• Induced by phenobarbital
109. Sulfate Conjugation
• Conducted by the soluble enzyme sulfotransferase
• Endogenous donor molecule to conjugation is
3’-phosphoadenosine-5’-phosphosulfate (PAPS)
• Conjugates are ethereal in character
• Noninducible
110. 3’-Phosphoadenosine-5’-phosphosulfate (PAPS)
The cytosolic enzyme sulfotransferase conducts the donation of
sulfate from the endogenously synthesized PAPS to various
substrates to form sulfate conjugates. An example of such substrate
is acetaminophen.
115. N-Acetyltransferase
• A soluble enzyme
• Isoniazid is a substrate
• Genetic variation occurs
– Some individuals are fast acetylators
– Some individuals are slow acetylators
• Acetyl coenzyme A is the endogenous donor
molecule
116. Acetyl CoA
Various acetylases, for examples, choline acetylase and N-acetyl
transferase, all soluble enzymes, conduct the transfer of the acetyl
group of acetyl CoA to various substrates. For example, N-acetylation
of isoniazid. Genetic polyporphism occurs with N-acetyltransferase.
122. S-Adenosylmethionine
Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and
phenylethanolamine-N-methyl transferase (PNMT) conducts the
donation of the methyl group from the endogenously synthesized SAM
to various substrates to form methylated conjugates. Norepinephrine is
N-methylated by PNMT to form epinephrine. Norepinephrine,
epinephrine, dopamine, and L-DOPA are O-methylated by COMT.
123. Methyltransferases
• A family of soluble enzymes that conducts
– N-methylation; N-CH3
– O-methylation; O-CH3
– S-methylation; S-CH3
• S-adenosylmethionine (SAM)is the endogenous donor
molecule. It is demethylated to S-adenosylhomocysteine
127. S-Methylation of 6-Mercaptopurine
TPMT - thiopurinemethyltransferase; some individuals are
deficient in this enzyme that is critically important for the
metabolism of this agent
128. METABOLISM OF MERCAPTOPURINE (1)
• TMPT -Thiomethylpurinetransferase
– Conducts S-methylation of the substrate
– Found in RBC’s
– Isoforms exist
• active enzyme
• inactive enzyme
6-Mercaptopurine 6-Methylmercaptopurine
TMPT
131. Multiple Metabolic Pathways Exist
for Aspirin’s Metabolism
Hydolysis of aspirin produces salicyclic acid, as
seen in the next slide
132. Salicyluric Acid is the Glycine Conjugate of Aspirin
Salicyluric acid, the glycine conjugate of salicyclic acid, is the main
metabolite of aspirin. Approximately 76% of aspirin is metabolized
through amino acid conjugation.
133. Acetyl Salicylic Acid (Aspirin) Metabolism
• Salicylic acid the hydrolytic product of acetyl salicylic
acid. Salicylic acid is further metabolized
• Salicyl uric acid is the glycine conjugate and the main
metabolite of aspirin. About 75% of aspirin is
metabolized by this pathway
• Other metabolites of aspirin
– the acyl glucuronide conjugate of salicylic acid (salicylic acid
glucuronide)
– the phenol glucuronide conjugate of salicylic acid (salicyl phenol
glucuronide)
– the ring hydroxylated product of salicylic acid (gentisic acid)
– the ring hydroxylated product of the glycine conjugate (gentisuric
acid
138. MERCAPTURIC ACID FORMATION
• Conjugation of substrate to glutathione by the
enzyme glutathione transferase
• Hydrolytic removal of glutamic acid by glutamyl
transpeptidase
• Hydrolytic removal of glycine by cysteinyl glycinase
• Acetylation of the cysteinyl substrate by
N-acetyltransferase to form the N-acetylated cysteinyl
conjugate of substrate; substrate referred to as a
“mercapturate”
141. ACETAMINOPHEN AND ITS PHASE II METABOLITES
The sulfate and glucuronide conjugates of acetaminophen are the major
metabolites. High doses of acetaminophen can exhaust the metabolic pathways
that produce these conjugates, allowing more of the parent drug to undergo the
phase I metabolic pathway which is involved in bioactivation and toxication.
143. ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2
The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen,
is always produced by microsomal cytochrome P450. It rearranges to
the electrophile N-acetylbenzoquinoneimine, which in turn reacts with
the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is
the final metabolite. If tissue glutathione stores are depleted as a result
of fasting, intake of excessive doses of acetaminophen or through
induction of CYP2E1 as a result of chronic intake of ethanol, the
quinone interacts with nucleophilic sites of cellular macromolecules,
such as proteins. Liver necrosis is the result. Regular intake of
acetaminophen during fasting or chronic ethanol intake should be
avoided. N-acetylcysteine is the antidote for acetaminophen poisoning.
It reacts with the electrophile. A small amount of acetaminophen is
reported to undergo deacetylation to the phase 1 metabolite p-
aminophenol.
147. Further Metabolism of N-HydroxyAAF Produces Cancer
N-HydroxyAAF undergoes phase II metabolism to the
ultimate carcingogen. The glucuronide pathway is also
involved in carcinogenesis
154. Factors Affecting Drug Metabolism
• Enzyme Induction - increased enzyme protein levels
in the cell
– Phenobarbital type induction by many drugs
– Polycyclic hydrocarbon type induction by
polycyclic hydrocarbons such as 3,4-benzopyrene
and 3-methylcholanthrene
158. FACTORS AFFECTING DRUG METABOLISM
• Diet
– Charcoal broiled foods (contain polycyclic
hydrocarbons that increase certain enzyme protein in
cells)
– Grapefruit juice (the active component is the
furancoumarin 6,7-dihydroxybergamottin which
inhibits a certain a group of microsomal enzymes)
165. FACTORS AFFECTING DRUG METABOLISM
• Gender
– Most studies are performed in the rat. In general,
male rats metabolize drugs faster than female rats
167. FACTORS AFFECTING DRUG METABOLISM
• Degree of protein binding
– Conditions that displace bound drug from protein
allows more of the drug to be accessible to the
enzyme for which it serves as a substrate e.g.
uremia, low plasma albumin
170. Factors Affecting Drug Metabolism
• Species variation
– Human beings metabolize amphetamine by
deamination; rats and dogs metabolize the drug by
aromatic hydroxylation
– Guinea pigs have very little sulfotransferase
activity, humans have substantial activity
– Guinea pigs do not N-hydroxylate substrates;
mice, rabbits, dogs do
– Hexobarbital is metabolized at different rates by
different species
173. Factors Affecting Drug Metabolism
• Substrate competition
– Two or more drugs competing for the same
enzyme can affect the metabolism of each other;
the substrate for which the enzyme has the
greater affinity would be preferentially metabolized