METABOLISM & TOXICOLOGY
Metabolism: chemical transformations that compounds undergo in the body
(biotransformation) = what does the body do to the compound.
Toxicology: adverse effects of chemicals on organisms = what does the compound to
the body.
Paracetamol is a common painkiller. It is considered safe when used within
recommended dosage limits. The maximum recommended dose is stated as 6
tablets (or 3 grams) per day. However, exceeding this limit may lead to adverse
effects. The deadly dose is considered to be around 30 grams.
Paracetamol is a lipophilic compound, which works after 30 minutes. This is
because it must be absorbed and distributed to the pharmaceutical target.
Paracetamol stops working after 6 hours due to a decrease in plasma levels. The
duration of action is influenced by factors such as metabolism and elimination.
Water-soluble compounds (hydrophilic) are inefficiently absorbed since they cannot
pass the lipophilic cell membranes. They may require transporters for their
absorption. Water-soluble compounds are easily excreted, since they are more
readily dissolved in the aqueous environment of urine, facilitating renal elimination.
Fat-soluble compounds (lipophilic) are not readily soluble in the aqueous
environment of blood. Once in the bloodstream, fat-soluble compounds, especially
those with high lipophilicity, may bind strongly to plasma proteins, particularly
albumin. This binding influences the distribution and transport of the compounds in
the blood. The excretion of lipophilic compounds can be slow due to protein binding,
so the clearance is low.
To enter cells passively, compounds need to pass membranes, and
therefore, must be lipophilic. But, to become excreted, compounds
need to be hydrophilic.
Metabolism transforms a lipophilic compound into a water-soluble
compound that can be excreted.
Paracetamol toxicity:
• 70 mg/kg → toxic effects (5 gram)
• 140 mg/kg → moderate liver damage (10 gram)
• 200 mg/kg → severe liver damage (14 gram)
• Chronic use: 3-4 g/day → liver damage
Toxicity can be enhanced by chronic alcohol use and by certain drugs such as
carbamazepine, isoniazid and barbiturates.
The antidote for paracetamol poisoning is N-acetylcysteine or methionine. These
compounds reduce the toxicity.
1
,Metabolites are more toxic than parent compound → toxification or bioactivation.
Metabolites are less toxic than parent compound → detoxification.
Every drug has a desirable effect or undesirable effect (side effect). A toxic effect may
sometimes be a desirable effect for other diseases. This can occur with off label
usage; the drug is prescribed for a purpose other than its officially approved
indication.
When a compound is toxic at pharmaceutical dose level, an adverse drug reaction
(ADR) occurs. An adverse drug reaction is any (unwanted) effect of a drug that
interferes with the normal function and/or adaptability of the body to (stimuli from) the
environment.
Drug targets:
• Receptors
• Other proteins; enzymes, transporters, etc.
• Membrane-lipids
• DNA/RNA
• Ca2+ homeostasis
• Ion channels
• Mitochondria (energy)
Adverse reactions can have different manifestations –
Local → Systemic
Rapid onset/acute → Delayed/chronic
Reversible → Irreversible
Gradual → All or nothing
Direct → Indirect
ADRs can result directly from the pharmaceutical action of the drug, but it can also be
an indirect result from secondary actions.
Adverse effects:
• Cell death/organ failure
• Pharmacological/physiological effects
• Genotoxicity = damage to genetic material
• Carcinogenicity = potential cancer cause
• Reproduction damage = damage to reproduction organs (infertility)
• Teratogenicity
• Neurotoxicity = damage to nervous system
• Immunotoxicity, sensitization
• Irritation (skin, eye)
Teratogenicity causes birth defects or abnormalities in the developing fetus when
exposed during pregnancy.
2
,Immunotoxicity: toxic effects mediated by the immune system. This can include
immunological responses to damage somewhere in the body. For example, (1)
sensitization, which refers to the process by which an individual becomes
hypersensitive or allergic to a particular substance. Or (2) the formation of haptens
(small molecules that can elicit an immune response), which can trigger immune-
mediated toxicity.
Toxic effects on the immune system itself: toxic effect on B- (responsible for
antibody production) or T- lymphocytes (involved in cell-mediated immunity).
Some drugs or substances have immunosuppressive or immunostimulants
properties, meaning they suppress the activity of the immune system or enhance the
activity of the immune system.
On-target toxicity occurs when the drug causes an
undesired effect at the intended target site.
For example: increased exposure of the target →
increased interaction of drug with target → toxicity
Off-target toxicity occurs when a drug interacts with
unintended targets in the body, leading to undesired
effects that are not related to the drug's primary
mechanism of action, but via a completely different
mechanism.
Off-target or on-target? –
• Liver necrosis due to paracetamol: off-target effect.
• Muscle toxicity due to HMG coA inhibition by statins: on-target effect.
• Low blood pressure due to beta blocker: on-target effect.
• Cardiotoxicity by anti-histamine drug terfenadine: off-target effect.
“All substances are poisons, it is the dose that makes the poison.”
Exposure-effect relationships –
Relationship between the level of exposure to a certain drug
and the resulting pharmacological or toxicological effect. For
all 3 drugs, it is true that the effect increases as the exposure
increases → dose-dependent relationship.
However, the 3 drugs differ in efficacy. At the end, they all
have the same exposure level, but compound B shows the
highest effect.
3
, Cumulative dose-response relationship –
Animals are treated with increasing doses of a drug that
causes, for instance, liver necrosis. The % of the animals
that show an effect at each dose can be determined and
plotted.
Y-axis: cumulative response (%)
X-axis: dose (mg/kg)
A special type of a dose-response curve is hormesis.
Hormesis suggests that a substance exhibits adverse
responses at both low and high dose.
• Low dose → deficiency → no therapeutic effect
• High dose → toxicity → side effects
Same dose ≠ same exposure –
Toxic effect depends on the concentration at the target, which is related to the dose,
but:
• Differences in exposure routes
• Species/interindividual differences in ADME
• Accumulation
• Interactions (induction, inhibition: e.g. on metabolizing enzymes)
These factors affect the individual exposure of the target.
The dose/exposure AND the compound characteristics determine
the toxicity.
LD50 is the dosage causing death in 50% of the exposed animals.
From this list, it can be seen that botulinum toxin is the most toxic
compound. Only 0.00001 mg botulinum toxin per kg body weight
leads to death in 50% of the animals.
However, there is a difference in toxicity between animals and
humans. E.g. the lethal dose of morphine in man is 2 mg/kg
instead of 900 mg/kg in animals.
The combination of dose and characteristics of the
compound can assess the toxicity/safety:
• Chemical and physical properties
• Biological effects
• Dose and systemic exposure
• Exposure of the target organ/tissue/cell
4
Metabolism: chemical transformations that compounds undergo in the body
(biotransformation) = what does the body do to the compound.
Toxicology: adverse effects of chemicals on organisms = what does the compound to
the body.
Paracetamol is a common painkiller. It is considered safe when used within
recommended dosage limits. The maximum recommended dose is stated as 6
tablets (or 3 grams) per day. However, exceeding this limit may lead to adverse
effects. The deadly dose is considered to be around 30 grams.
Paracetamol is a lipophilic compound, which works after 30 minutes. This is
because it must be absorbed and distributed to the pharmaceutical target.
Paracetamol stops working after 6 hours due to a decrease in plasma levels. The
duration of action is influenced by factors such as metabolism and elimination.
Water-soluble compounds (hydrophilic) are inefficiently absorbed since they cannot
pass the lipophilic cell membranes. They may require transporters for their
absorption. Water-soluble compounds are easily excreted, since they are more
readily dissolved in the aqueous environment of urine, facilitating renal elimination.
Fat-soluble compounds (lipophilic) are not readily soluble in the aqueous
environment of blood. Once in the bloodstream, fat-soluble compounds, especially
those with high lipophilicity, may bind strongly to plasma proteins, particularly
albumin. This binding influences the distribution and transport of the compounds in
the blood. The excretion of lipophilic compounds can be slow due to protein binding,
so the clearance is low.
To enter cells passively, compounds need to pass membranes, and
therefore, must be lipophilic. But, to become excreted, compounds
need to be hydrophilic.
Metabolism transforms a lipophilic compound into a water-soluble
compound that can be excreted.
Paracetamol toxicity:
• 70 mg/kg → toxic effects (5 gram)
• 140 mg/kg → moderate liver damage (10 gram)
• 200 mg/kg → severe liver damage (14 gram)
• Chronic use: 3-4 g/day → liver damage
Toxicity can be enhanced by chronic alcohol use and by certain drugs such as
carbamazepine, isoniazid and barbiturates.
The antidote for paracetamol poisoning is N-acetylcysteine or methionine. These
compounds reduce the toxicity.
1
,Metabolites are more toxic than parent compound → toxification or bioactivation.
Metabolites are less toxic than parent compound → detoxification.
Every drug has a desirable effect or undesirable effect (side effect). A toxic effect may
sometimes be a desirable effect for other diseases. This can occur with off label
usage; the drug is prescribed for a purpose other than its officially approved
indication.
When a compound is toxic at pharmaceutical dose level, an adverse drug reaction
(ADR) occurs. An adverse drug reaction is any (unwanted) effect of a drug that
interferes with the normal function and/or adaptability of the body to (stimuli from) the
environment.
Drug targets:
• Receptors
• Other proteins; enzymes, transporters, etc.
• Membrane-lipids
• DNA/RNA
• Ca2+ homeostasis
• Ion channels
• Mitochondria (energy)
Adverse reactions can have different manifestations –
Local → Systemic
Rapid onset/acute → Delayed/chronic
Reversible → Irreversible
Gradual → All or nothing
Direct → Indirect
ADRs can result directly from the pharmaceutical action of the drug, but it can also be
an indirect result from secondary actions.
Adverse effects:
• Cell death/organ failure
• Pharmacological/physiological effects
• Genotoxicity = damage to genetic material
• Carcinogenicity = potential cancer cause
• Reproduction damage = damage to reproduction organs (infertility)
• Teratogenicity
• Neurotoxicity = damage to nervous system
• Immunotoxicity, sensitization
• Irritation (skin, eye)
Teratogenicity causes birth defects or abnormalities in the developing fetus when
exposed during pregnancy.
2
,Immunotoxicity: toxic effects mediated by the immune system. This can include
immunological responses to damage somewhere in the body. For example, (1)
sensitization, which refers to the process by which an individual becomes
hypersensitive or allergic to a particular substance. Or (2) the formation of haptens
(small molecules that can elicit an immune response), which can trigger immune-
mediated toxicity.
Toxic effects on the immune system itself: toxic effect on B- (responsible for
antibody production) or T- lymphocytes (involved in cell-mediated immunity).
Some drugs or substances have immunosuppressive or immunostimulants
properties, meaning they suppress the activity of the immune system or enhance the
activity of the immune system.
On-target toxicity occurs when the drug causes an
undesired effect at the intended target site.
For example: increased exposure of the target →
increased interaction of drug with target → toxicity
Off-target toxicity occurs when a drug interacts with
unintended targets in the body, leading to undesired
effects that are not related to the drug's primary
mechanism of action, but via a completely different
mechanism.
Off-target or on-target? –
• Liver necrosis due to paracetamol: off-target effect.
• Muscle toxicity due to HMG coA inhibition by statins: on-target effect.
• Low blood pressure due to beta blocker: on-target effect.
• Cardiotoxicity by anti-histamine drug terfenadine: off-target effect.
“All substances are poisons, it is the dose that makes the poison.”
Exposure-effect relationships –
Relationship between the level of exposure to a certain drug
and the resulting pharmacological or toxicological effect. For
all 3 drugs, it is true that the effect increases as the exposure
increases → dose-dependent relationship.
However, the 3 drugs differ in efficacy. At the end, they all
have the same exposure level, but compound B shows the
highest effect.
3
, Cumulative dose-response relationship –
Animals are treated with increasing doses of a drug that
causes, for instance, liver necrosis. The % of the animals
that show an effect at each dose can be determined and
plotted.
Y-axis: cumulative response (%)
X-axis: dose (mg/kg)
A special type of a dose-response curve is hormesis.
Hormesis suggests that a substance exhibits adverse
responses at both low and high dose.
• Low dose → deficiency → no therapeutic effect
• High dose → toxicity → side effects
Same dose ≠ same exposure –
Toxic effect depends on the concentration at the target, which is related to the dose,
but:
• Differences in exposure routes
• Species/interindividual differences in ADME
• Accumulation
• Interactions (induction, inhibition: e.g. on metabolizing enzymes)
These factors affect the individual exposure of the target.
The dose/exposure AND the compound characteristics determine
the toxicity.
LD50 is the dosage causing death in 50% of the exposed animals.
From this list, it can be seen that botulinum toxin is the most toxic
compound. Only 0.00001 mg botulinum toxin per kg body weight
leads to death in 50% of the animals.
However, there is a difference in toxicity between animals and
humans. E.g. the lethal dose of morphine in man is 2 mg/kg
instead of 900 mg/kg in animals.
The combination of dose and characteristics of the
compound can assess the toxicity/safety:
• Chemical and physical properties
• Biological effects
• Dose and systemic exposure
• Exposure of the target organ/tissue/cell
4
