Marieke Wolf Metabolism and Toxicology 2024-2025
Metabolism and Toxicology
1
,Marieke Wolf Metabolism and Toxicology 2024-2025
Lecture 1
Definitions
Metabolism - Chemical transformations that compounds undergo in the body
(=biotransformation)
Toxicology – what does the compound do to the body (Adverse effects of chemicals on
organisms)
Pharmaceutical Compounds
• Lipophilic
o Pass the cell membrane
o E.g. paracetamol
• Hydrophilic
o Compounds can be easily excreted via the kidneys
o Transformation in the liver via metabolism
• ADME: absorption, distribution, metabolism, excretion
• Protein Binding
o Bind to albumin in the blood making it hard to excrete
o Large protein (cannot be eliminated via the kidney)
Paracetamol
• Working mechanism not known
• Safe dosage = 3g/day
• Deadly dosage = 30g/day
• Lipophilic
• Toxification due to metabolism
o N-OH group is an electrophile so it reacts very well in the body
• Balance between toxification (bioactivation) and detoxification
Adverse drug reaction (ADR)
• Any (unwanted) effect of a drug that interferes with normal body function
Targets
• Receptors
• Other proteins: enzymes, transporters etc.
• membrane-lipids
• DNA/RNA
• Ca2+ homeostasis
• Ion channels
• mitochondria (energy)
Effects
• Local OR systemic (taken up into the entire body but then acts toxic in any way also
specific)
• Rapid onset/acute OR delayed/chronic
• Reversible OR irreversible
• Gradual OR all or nothing
• Direct OR indirect
2
,Marieke Wolf Metabolism and Toxicology 2024-2025
Toxicity
• On-target toxicity
o Exaggerated pharmacological effect
o E.g.: Low blood pressure due to beta blockers, Myo (=muscle) toxicity due to
HMG CoA inhibition by statins
• Off target toxicity
o Toxicity via completely different mechanism than pharmacological effect
o E.g.: liver necrosis due to paracetamol, Cardiotoxicity by anti-histamine drug
terfenadine, penicillin hypersensitivity (is supposed to act on bacteria but acts
on blood for immune hypersensitivity)
• Depends on
o Concentration at the target and dosage (exposure)
o Characteristics of the compound
Can explain the concepts of hazard, risk and safety
Hazard: Something that has the potential to harm you (biological property/potential)
Risk: The likelihood of a hazard causing harm (chance of toxicity)
Safety: The prevention of a hazard or decrease of risk
Can explain the terms LD50, TD50/TC50, ED50/EC50, TI, NOAEL, LOAEL, ADI and MOS
Measure of toxicity
LD50: lethal dose
TD50/TC50: toxicity dose/concentration
ED50/EC50: effective dose or concentration
TI: therapeutic index = TD50/ED50
NOAEL: no adverse effect level
LOAEL: lowest observed adverse effect level
ADI: acceptable daily intake = NOAEL/safety factor
MOS: margin of safety = TD01/TD99
ADR: adverse drug reactions
Knows in which phase of drug development which toxicity tests are performed
• Research phase
o Screening metabolism ad toxicity via HTP (high throughput screening)
• Development stage
o 2 test animal species
Can explain the role of EMA / FDA / CBG in risk assessment of pharmaceutical drugs
• Oversee clinical trials and make sure procedure is up to standards
3
, Marieke Wolf Metabolism and Toxicology 2024-2025
Lecture 2 – ADME and Toxicology
ADME
• Absorption
o Where how much
• Distribution
o How much where to
• Metabolism
o Which products
• Elimination
o Where how much
Toxicity
• Local toxicity
o Harmful without being fully absorbed
• Systemic toxicity
o Harmful after absorption into general circulation
o Can still be local
• Bioavailability
o Fraction of dose that reaches the circulation
o F=AUC(oral) / AUC(IV)
Absorption
• Oral administration
o Epithelial cells of the intestinal wall
o Large surface area
o Dependent on:
▪ pH, blood flow, metabolism, transport, nutrition, contractions
▪ Lipophilicity, affinity for carriers, size, solubility, affinity for
excretion carriers (P-gp)
• Rectal administration
o Epithelial cells of the rectum
• Dermal administration
o Epithelial skin cells
• Pulmonary administration
o Airway epithelial cells
First-pass effect
• Loss via liver and lumen metabolism
Skin absorption
• Large surface area
• Dependence:
o Thickness, damage, hydration, blood flow, metabolism in skin,
lipophilicity
4
Metabolism and Toxicology
1
,Marieke Wolf Metabolism and Toxicology 2024-2025
Lecture 1
Definitions
Metabolism - Chemical transformations that compounds undergo in the body
(=biotransformation)
Toxicology – what does the compound do to the body (Adverse effects of chemicals on
organisms)
Pharmaceutical Compounds
• Lipophilic
o Pass the cell membrane
o E.g. paracetamol
• Hydrophilic
o Compounds can be easily excreted via the kidneys
o Transformation in the liver via metabolism
• ADME: absorption, distribution, metabolism, excretion
• Protein Binding
o Bind to albumin in the blood making it hard to excrete
o Large protein (cannot be eliminated via the kidney)
Paracetamol
• Working mechanism not known
• Safe dosage = 3g/day
• Deadly dosage = 30g/day
• Lipophilic
• Toxification due to metabolism
o N-OH group is an electrophile so it reacts very well in the body
• Balance between toxification (bioactivation) and detoxification
Adverse drug reaction (ADR)
• Any (unwanted) effect of a drug that interferes with normal body function
Targets
• Receptors
• Other proteins: enzymes, transporters etc.
• membrane-lipids
• DNA/RNA
• Ca2+ homeostasis
• Ion channels
• mitochondria (energy)
Effects
• Local OR systemic (taken up into the entire body but then acts toxic in any way also
specific)
• Rapid onset/acute OR delayed/chronic
• Reversible OR irreversible
• Gradual OR all or nothing
• Direct OR indirect
2
,Marieke Wolf Metabolism and Toxicology 2024-2025
Toxicity
• On-target toxicity
o Exaggerated pharmacological effect
o E.g.: Low blood pressure due to beta blockers, Myo (=muscle) toxicity due to
HMG CoA inhibition by statins
• Off target toxicity
o Toxicity via completely different mechanism than pharmacological effect
o E.g.: liver necrosis due to paracetamol, Cardiotoxicity by anti-histamine drug
terfenadine, penicillin hypersensitivity (is supposed to act on bacteria but acts
on blood for immune hypersensitivity)
• Depends on
o Concentration at the target and dosage (exposure)
o Characteristics of the compound
Can explain the concepts of hazard, risk and safety
Hazard: Something that has the potential to harm you (biological property/potential)
Risk: The likelihood of a hazard causing harm (chance of toxicity)
Safety: The prevention of a hazard or decrease of risk
Can explain the terms LD50, TD50/TC50, ED50/EC50, TI, NOAEL, LOAEL, ADI and MOS
Measure of toxicity
LD50: lethal dose
TD50/TC50: toxicity dose/concentration
ED50/EC50: effective dose or concentration
TI: therapeutic index = TD50/ED50
NOAEL: no adverse effect level
LOAEL: lowest observed adverse effect level
ADI: acceptable daily intake = NOAEL/safety factor
MOS: margin of safety = TD01/TD99
ADR: adverse drug reactions
Knows in which phase of drug development which toxicity tests are performed
• Research phase
o Screening metabolism ad toxicity via HTP (high throughput screening)
• Development stage
o 2 test animal species
Can explain the role of EMA / FDA / CBG in risk assessment of pharmaceutical drugs
• Oversee clinical trials and make sure procedure is up to standards
3
, Marieke Wolf Metabolism and Toxicology 2024-2025
Lecture 2 – ADME and Toxicology
ADME
• Absorption
o Where how much
• Distribution
o How much where to
• Metabolism
o Which products
• Elimination
o Where how much
Toxicity
• Local toxicity
o Harmful without being fully absorbed
• Systemic toxicity
o Harmful after absorption into general circulation
o Can still be local
• Bioavailability
o Fraction of dose that reaches the circulation
o F=AUC(oral) / AUC(IV)
Absorption
• Oral administration
o Epithelial cells of the intestinal wall
o Large surface area
o Dependent on:
▪ pH, blood flow, metabolism, transport, nutrition, contractions
▪ Lipophilicity, affinity for carriers, size, solubility, affinity for
excretion carriers (P-gp)
• Rectal administration
o Epithelial cells of the rectum
• Dermal administration
o Epithelial skin cells
• Pulmonary administration
o Airway epithelial cells
First-pass effect
• Loss via liver and lumen metabolism
Skin absorption
• Large surface area
• Dependence:
o Thickness, damage, hydration, blood flow, metabolism in skin,
lipophilicity
4
