METOX
,Contents
Metox...............................................................................................................................................5
Lecture 1..........................................................................................................................................7
Learning outcomes......................................................................................................................7
The faith of pharmaceutical in our body (ADME)........................................................................8
Relationship between Metabolism and toxicology.....................................................................9
Learning outcomes:...................................................................................................................10
Paracetamol...........................................................................................................................11
Learning outcomes:...................................................................................................................13
Lecture 12......................................................................................................................................18
Safety assessment......................................................................................................................18
Lecture 2........................................................................................................................................20
Chemical safety..........................................................................................................................20
Toxicokinetic..........................................................................................................................20
Kind of toxicity.......................................................................................................................20
Absorption.............................................................................................................................20
Distribution............................................................................................................................22
Excretion................................................................................................................................23
Learning objectives absorption..................................................................................................24
Learning objectives distribution................................................................................................29
Lecture 3........................................................................................................................................33
Learning outcomes: Phase 1 metabolism..............................................................................36
Reproduce the most common chemical reactions (hydrolysis / oxidation / reduction) of phase
I metabolism..............................................................................................................................36
Explain the possible consequences of metabolism for a drug with regard to excretion, activity
and / or toxicity..........................................................................................................................36
List important enzymes and cofactors involved in Phase I metabolism and mention the
location of these enzymes in the cell........................................................................................37
Explain the effect of epoxide hydrolase as a detoxification enzyme........................................37
Explain the function of the hydrolysis enzyme acetylcholinesterase and explain the
consequence of inhibition of this enzyme.................................................................................37
, Learning outcomes of Phase II metabolism...........................................................................40
Metabolism of Xenobiotics....................................................................................................43
Metabolism Phases................................................................................................................45
Lecture 4 (Inge)..............................................................................................................................52
Theory........................................................................................................................................53
Toxicity...................................................................................................................................53
Variation in Metabolism........................................................................................................54
Multiple interactions possible at the same time!..................................................................61
The “ethanol and paracetamol” paradox..............................................................................61
Lecture 5........................................................................................................................................62
Lecture outcomes..................................................................................................................62
Liver anatomy............................................................................................................................64
The liver contains multiple cell types: multicellular reactions..............................................65
Liver toxicity...............................................................................................................................66
Detection of liver damage in vivo..........................................................................................69
Lecture 6........................................................................................................................................71
Theory........................................................................................................................................71
4 steps leading to toxicity......................................................................................................71
Idiosyncratic toxicity = unpredictable toxicity.......................................................................74
Biomarkers used to detect toxicity........................................................................................74
Lecture 7........................................................................................................................................76
Oxidative stress..........................................................................................................................76
Detoxification of ROS and radicals.........................................................................................77
Glutathione to protect against cell damage..........................................................................78
Effects of oxidative stress:.....................................................................................................78
Lecture 8........................................................................................................................................80
Kidney components...................................................................................................................80
Nephron components................................................................................................................80
Glomerulus.............................................................................................................................80
Tubule....................................................................................................................................81
Loop of Henle.........................................................................................................................81
, Kidney toxicity............................................................................................................................82
Reduction in GFR....................................................................................................................82
Damage to proximal tubule cells...........................................................................................83
Nephrotoxic compounds...........................................................................................................84
Formation and degradation of glutathione conjugate..........................................................84
Toxification by CS-lyase in the kidney....................................................................................84
Kidney toxicity caused by APAP-GSH conjugates from the liver...........................................84
Kidney toxicity caused by Cisplatin........................................................................................84
NSAIDS...................................................................................................................................85
Cyclosporin.............................................................................................................................85
Aminoglycosides....................................................................................................................85
Lactam antibiotics..................................................................................................................85
Biomarkers and methods to measure renal toxicity.................................................................86
Lecture 9........................................................................................................................................88
Definitions..................................................................................................................................88
Classes of carcinogens...............................................................................................................88
Genotoxic...............................................................................................................................88
non-genotoxic........................................................................................................................89
Characteristics of the 3 stages...................................................................................................89
Initiation stage.......................................................................................................................89
Promotion stage.....................................................................................................................90
Progression............................................................................................................................90
Genetic toxicity..........................................................................................................................90
Genetic toxicity Different levels:............................................................................................91
DNA repair mechanisms:.......................................................................................................93
How to test for carcinogenesis..................................................................................................94
Additional information...............................................................................................................94
How to test for carcinogenesis..............................................................................................94
Lecture 10: Cardiotoxicity..............................................................................................................96
General information about the heart........................................................................................96
Electrocardiogram (ECG)........................................................................................................97
, Cardiotoxicity.............................................................................................................................99
Drug induced cardiotoxicity...................................................................................................99
Neurotoxicity...........................................................................................................................102
General old information related to neurons.......................................................................102
Cells......................................................................................................................................102
blood-brain barrier..............................................................................................................103
Axonal transport..................................................................................................................103
mechanisms of neurotoxicity..............................................................................................105
Alteration of neurotransmission..........................................................................................106
Mechanisms of perturbation:..............................................................................................107
Alteration of neurotransmission..........................................................................................107
Drug induced neurotoxicity.................................................................................................107
Methods to test neurotoxicity.............................................................................................108
Lecture 11: Reproductive and developmental toxicology...........................................................109
Thalidomide = Softenon...........................................................................................................109
Learning outcomes..................................................................................................................109
Terminology.............................................................................................................................111
Principles of developmental toxicology...................................................................................112
Related to the physiology....................................................................................................112
Related to teratogen agents' effects on the physiology......................................................114
The 3 compartments................................................................................................................115
1)Mother..............................................................................................................................115
2) Placenta...........................................................................................................................115
3) fetus.................................................................................................................................116
Methods for toxicity testing: animal models...........................................................................116
Segment I: fertility and general reproduction study...........................................................116
Segment II: teratogenicity test............................................................................................116
Segment III: peri- and postnatal development....................................................................116
Teratogenic effects:.................................................................................................................117
Paternal teratogenesis:............................................................................................................117
,Metox
› Exam
In the Aletta Jacobs Halls, Friday 27/1, 18.15-20.15
›
Lecturers:
Dr. Inge de Graaf: Chapters 1, 2, 4, 6,13,14
Dr. Anna Salvati: Chapter 3, 8+cardiotoxicity+neurotoxicity
Dr. Anika Nagelkerke: 10
Prof. Dr. P. Olinga: 5, 6,13, Risk assessment in Pharmaceutical industry
,
,Lecture 1.
Learning outcomes
Explain the relationship between ADM(etabolism)E and Toxicity✅
The relationship between ADME (Absorption, Distribution, Metabolism, and Excretion)
and toxicity is an important one. ADME is the process by which a drug is absorbed,
distributed, metabolized, and excreted from the body. This process is essential for the
safe and effective use of drugs. Toxicity, on the other hand, is the potential for a drug to
cause harm to the body.
The metabolism of a drug is an important factor in determining its toxicity.
Metabolism can facilitate the excretion of a lipophilic substance, which can reduce its
toxicity. However, metabolism can also cause toxicity.
For example, paracetamol is metabolized to a toxic metabolite, which can cause
liver damage. The toxicokinetics of a drug also plays an important role in
determining its toxicity. Toxicokinetics is the study of how a drug is absorbed,
distributed, metabolized, and excreted from the body. Factors such as the route of
administration, the properties of the drug, and the presence of transporters can all
influence the toxicokinetics of a drug and thus its toxicity.
In conclusion, the relationship between ADME and toxicity is an important one.
Metabolism can both facilitate the excretion of a lipophilic substance and cause
toxicity. Toxicokinetics is also an important factor in determining the toxicity of a
drug.
Explain how metabolism can facilitate excretion of a lipophilic substance✅
Metabolism can facilitate the excretion of a lipophilic substance by breaking down the
substance into smaller, more water-soluble molecules. This process is known as
biotransformation. The smaller molecules are then more easily excreted through the
kidneys, liver, and other organs. Metabolism can also increase the solubility of the
lipophilic substance, making it easier for the body to excrete it. Additionally, metabolism
can increase the rate of excretion by increasing the number of molecules that can be
excreted at once. This is known as metabolic clearance. Finally, metabolism can also
increase the rate of excretion by increasing the number of molecules that can be excreted
at once. This is known as metabolic clearance
Explain how metabolism can cause toxicity with paracetamol as an example✅
Metabolism can cause toxicity with paracetamol as an example by the formation of
reactive metabolites. Paracetamol is metabolized in the liver by the cytochrome P450
enzyme system, which is responsible for the formation of a toxic metabolite called N-
acetyl-p-benzoquinoneimine (NAPQI). NAPQI is a highly reactive metabolite that can
covalently bind to cellular targets, such as proteins, lipids, and DNA, leading to cell death
and tissue damage. This can result in liver toxicity, which can be fatal if left untreated.
Variations in the metabolism of paracetamol can also lead to differences in toxicity
between individuals, as well as between species. Factors such as age, gender, genetics,
and drug interactions can all influence the metabolism of paracetamol and thus its
, toxicity. Inhibition of the cytochrome P450 enzyme system can also lead to increased
levels of paracetamol in the body, resulting in increased toxicity.
The faith of
pharmaceutical in our
body (ADME)
Drug as a pill/drink/cream
1. Absorption = Uptake in blood
2. Distribution = Distribution in the body to organs and tissues after systemic uptake
a. Why do drug need to be also lipophilc?
To enter cells compounds need to pass membranes and need to be
lipophilic
Further more charged drug
can not pass the
membrane
3. Metabolism = Transformation other
compounds
4. Excretion = In urine or feces
, Relationship
between Metabolism
and toxicology
What is metabolism?
Metabolism: chemical transformations, which is mainly making it more
hydrophilic in order to excrete it via the kidneys
By enzymes
Why is metabolism important?
It transforms the form of the drug to excrete it from the body ((verandert (vaak)
toxiciteit en effectiviteit van een stof ))
Compounds need to be water-soluble (hydrophilic) enough to be excreted
where is that done?
By Liver: the liver transforms the hydrophobic drug into
hydrophilic
Toxicology: adverse effects of chemicals on organisms
Xenobiotics: these are compounds that are not natural to the body
The can be naturally formed in the nature or can be made in the
lab
How can therapeutic compounds
reach their targets?
By Passing membranes
Drug conditions
Lipophilic enough
why is lipophilicity important?
To pass the membrane
Binding to albumin, which is a plasma protein, Reduce
clearance in other words: lipophilic product cannot easily be
excreted
If the drug is not lipophilic enough it is too hydrophilic
,Contents
Metox...............................................................................................................................................5
Lecture 1..........................................................................................................................................7
Learning outcomes......................................................................................................................7
The faith of pharmaceutical in our body (ADME)........................................................................8
Relationship between Metabolism and toxicology.....................................................................9
Learning outcomes:...................................................................................................................10
Paracetamol...........................................................................................................................11
Learning outcomes:...................................................................................................................13
Lecture 12......................................................................................................................................18
Safety assessment......................................................................................................................18
Lecture 2........................................................................................................................................20
Chemical safety..........................................................................................................................20
Toxicokinetic..........................................................................................................................20
Kind of toxicity.......................................................................................................................20
Absorption.............................................................................................................................20
Distribution............................................................................................................................22
Excretion................................................................................................................................23
Learning objectives absorption..................................................................................................24
Learning objectives distribution................................................................................................29
Lecture 3........................................................................................................................................33
Learning outcomes: Phase 1 metabolism..............................................................................36
Reproduce the most common chemical reactions (hydrolysis / oxidation / reduction) of phase
I metabolism..............................................................................................................................36
Explain the possible consequences of metabolism for a drug with regard to excretion, activity
and / or toxicity..........................................................................................................................36
List important enzymes and cofactors involved in Phase I metabolism and mention the
location of these enzymes in the cell........................................................................................37
Explain the effect of epoxide hydrolase as a detoxification enzyme........................................37
Explain the function of the hydrolysis enzyme acetylcholinesterase and explain the
consequence of inhibition of this enzyme.................................................................................37
, Learning outcomes of Phase II metabolism...........................................................................40
Metabolism of Xenobiotics....................................................................................................43
Metabolism Phases................................................................................................................45
Lecture 4 (Inge)..............................................................................................................................52
Theory........................................................................................................................................53
Toxicity...................................................................................................................................53
Variation in Metabolism........................................................................................................54
Multiple interactions possible at the same time!..................................................................61
The “ethanol and paracetamol” paradox..............................................................................61
Lecture 5........................................................................................................................................62
Lecture outcomes..................................................................................................................62
Liver anatomy............................................................................................................................64
The liver contains multiple cell types: multicellular reactions..............................................65
Liver toxicity...............................................................................................................................66
Detection of liver damage in vivo..........................................................................................69
Lecture 6........................................................................................................................................71
Theory........................................................................................................................................71
4 steps leading to toxicity......................................................................................................71
Idiosyncratic toxicity = unpredictable toxicity.......................................................................74
Biomarkers used to detect toxicity........................................................................................74
Lecture 7........................................................................................................................................76
Oxidative stress..........................................................................................................................76
Detoxification of ROS and radicals.........................................................................................77
Glutathione to protect against cell damage..........................................................................78
Effects of oxidative stress:.....................................................................................................78
Lecture 8........................................................................................................................................80
Kidney components...................................................................................................................80
Nephron components................................................................................................................80
Glomerulus.............................................................................................................................80
Tubule....................................................................................................................................81
Loop of Henle.........................................................................................................................81
, Kidney toxicity............................................................................................................................82
Reduction in GFR....................................................................................................................82
Damage to proximal tubule cells...........................................................................................83
Nephrotoxic compounds...........................................................................................................84
Formation and degradation of glutathione conjugate..........................................................84
Toxification by CS-lyase in the kidney....................................................................................84
Kidney toxicity caused by APAP-GSH conjugates from the liver...........................................84
Kidney toxicity caused by Cisplatin........................................................................................84
NSAIDS...................................................................................................................................85
Cyclosporin.............................................................................................................................85
Aminoglycosides....................................................................................................................85
Lactam antibiotics..................................................................................................................85
Biomarkers and methods to measure renal toxicity.................................................................86
Lecture 9........................................................................................................................................88
Definitions..................................................................................................................................88
Classes of carcinogens...............................................................................................................88
Genotoxic...............................................................................................................................88
non-genotoxic........................................................................................................................89
Characteristics of the 3 stages...................................................................................................89
Initiation stage.......................................................................................................................89
Promotion stage.....................................................................................................................90
Progression............................................................................................................................90
Genetic toxicity..........................................................................................................................90
Genetic toxicity Different levels:............................................................................................91
DNA repair mechanisms:.......................................................................................................93
How to test for carcinogenesis..................................................................................................94
Additional information...............................................................................................................94
How to test for carcinogenesis..............................................................................................94
Lecture 10: Cardiotoxicity..............................................................................................................96
General information about the heart........................................................................................96
Electrocardiogram (ECG)........................................................................................................97
, Cardiotoxicity.............................................................................................................................99
Drug induced cardiotoxicity...................................................................................................99
Neurotoxicity...........................................................................................................................102
General old information related to neurons.......................................................................102
Cells......................................................................................................................................102
blood-brain barrier..............................................................................................................103
Axonal transport..................................................................................................................103
mechanisms of neurotoxicity..............................................................................................105
Alteration of neurotransmission..........................................................................................106
Mechanisms of perturbation:..............................................................................................107
Alteration of neurotransmission..........................................................................................107
Drug induced neurotoxicity.................................................................................................107
Methods to test neurotoxicity.............................................................................................108
Lecture 11: Reproductive and developmental toxicology...........................................................109
Thalidomide = Softenon...........................................................................................................109
Learning outcomes..................................................................................................................109
Terminology.............................................................................................................................111
Principles of developmental toxicology...................................................................................112
Related to the physiology....................................................................................................112
Related to teratogen agents' effects on the physiology......................................................114
The 3 compartments................................................................................................................115
1)Mother..............................................................................................................................115
2) Placenta...........................................................................................................................115
3) fetus.................................................................................................................................116
Methods for toxicity testing: animal models...........................................................................116
Segment I: fertility and general reproduction study...........................................................116
Segment II: teratogenicity test............................................................................................116
Segment III: peri- and postnatal development....................................................................116
Teratogenic effects:.................................................................................................................117
Paternal teratogenesis:............................................................................................................117
,Metox
› Exam
In the Aletta Jacobs Halls, Friday 27/1, 18.15-20.15
›
Lecturers:
Dr. Inge de Graaf: Chapters 1, 2, 4, 6,13,14
Dr. Anna Salvati: Chapter 3, 8+cardiotoxicity+neurotoxicity
Dr. Anika Nagelkerke: 10
Prof. Dr. P. Olinga: 5, 6,13, Risk assessment in Pharmaceutical industry
,
,Lecture 1.
Learning outcomes
Explain the relationship between ADM(etabolism)E and Toxicity✅
The relationship between ADME (Absorption, Distribution, Metabolism, and Excretion)
and toxicity is an important one. ADME is the process by which a drug is absorbed,
distributed, metabolized, and excreted from the body. This process is essential for the
safe and effective use of drugs. Toxicity, on the other hand, is the potential for a drug to
cause harm to the body.
The metabolism of a drug is an important factor in determining its toxicity.
Metabolism can facilitate the excretion of a lipophilic substance, which can reduce its
toxicity. However, metabolism can also cause toxicity.
For example, paracetamol is metabolized to a toxic metabolite, which can cause
liver damage. The toxicokinetics of a drug also plays an important role in
determining its toxicity. Toxicokinetics is the study of how a drug is absorbed,
distributed, metabolized, and excreted from the body. Factors such as the route of
administration, the properties of the drug, and the presence of transporters can all
influence the toxicokinetics of a drug and thus its toxicity.
In conclusion, the relationship between ADME and toxicity is an important one.
Metabolism can both facilitate the excretion of a lipophilic substance and cause
toxicity. Toxicokinetics is also an important factor in determining the toxicity of a
drug.
Explain how metabolism can facilitate excretion of a lipophilic substance✅
Metabolism can facilitate the excretion of a lipophilic substance by breaking down the
substance into smaller, more water-soluble molecules. This process is known as
biotransformation. The smaller molecules are then more easily excreted through the
kidneys, liver, and other organs. Metabolism can also increase the solubility of the
lipophilic substance, making it easier for the body to excrete it. Additionally, metabolism
can increase the rate of excretion by increasing the number of molecules that can be
excreted at once. This is known as metabolic clearance. Finally, metabolism can also
increase the rate of excretion by increasing the number of molecules that can be excreted
at once. This is known as metabolic clearance
Explain how metabolism can cause toxicity with paracetamol as an example✅
Metabolism can cause toxicity with paracetamol as an example by the formation of
reactive metabolites. Paracetamol is metabolized in the liver by the cytochrome P450
enzyme system, which is responsible for the formation of a toxic metabolite called N-
acetyl-p-benzoquinoneimine (NAPQI). NAPQI is a highly reactive metabolite that can
covalently bind to cellular targets, such as proteins, lipids, and DNA, leading to cell death
and tissue damage. This can result in liver toxicity, which can be fatal if left untreated.
Variations in the metabolism of paracetamol can also lead to differences in toxicity
between individuals, as well as between species. Factors such as age, gender, genetics,
and drug interactions can all influence the metabolism of paracetamol and thus its
, toxicity. Inhibition of the cytochrome P450 enzyme system can also lead to increased
levels of paracetamol in the body, resulting in increased toxicity.
The faith of
pharmaceutical in our
body (ADME)
Drug as a pill/drink/cream
1. Absorption = Uptake in blood
2. Distribution = Distribution in the body to organs and tissues after systemic uptake
a. Why do drug need to be also lipophilc?
To enter cells compounds need to pass membranes and need to be
lipophilic
Further more charged drug
can not pass the
membrane
3. Metabolism = Transformation other
compounds
4. Excretion = In urine or feces
, Relationship
between Metabolism
and toxicology
What is metabolism?
Metabolism: chemical transformations, which is mainly making it more
hydrophilic in order to excrete it via the kidneys
By enzymes
Why is metabolism important?
It transforms the form of the drug to excrete it from the body ((verandert (vaak)
toxiciteit en effectiviteit van een stof ))
Compounds need to be water-soluble (hydrophilic) enough to be excreted
where is that done?
By Liver: the liver transforms the hydrophobic drug into
hydrophilic
Toxicology: adverse effects of chemicals on organisms
Xenobiotics: these are compounds that are not natural to the body
The can be naturally formed in the nature or can be made in the
lab
How can therapeutic compounds
reach their targets?
By Passing membranes
Drug conditions
Lipophilic enough
why is lipophilicity important?
To pass the membrane
Binding to albumin, which is a plasma protein, Reduce
clearance in other words: lipophilic product cannot easily be
excreted
If the drug is not lipophilic enough it is too hydrophilic
