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Summary of all the lectures of metabolism and toxicology
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Summary of all the lectures of metabolism and toxicology
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Metabolism and ToxicologyLecture 1 van der Graaf
15/11/2019
Metabolism: the chemical transformation that compounds undergo in the body what does the
body do to a compound.
Toxicology: the adverse effects of chemicals on organisms what does the compound do to the
body.
Paracetamol is a very safe painkiller, but 30 grams dose is deadly. Toxicity has to do something with
its metabolism. It is a lipophilic compound. Paracetamol does not work immediately, because it
needs to be absorbed first. After 6 hours it is excreted no function anymore.
Drugs often are lipophilic in order to pass membranes. When they are ionized they do not pass
membranes easy anymore.
Water-soluble compounds are inefficiently absorbed (no good passing of the membranes) and are
very easily eliminated in the kidney again. Fat-soluble compounds are taken up quite efficiently, but
it can keep circulating in your body for a very long time.
Lipophilic compounds bind to proteins, to get soluble. They are not excreted when bound to the
protein, because the protein is quite big and this cannot pass the filter no excretion. Compounds
are not always completely bound to a protein. The unbound fraction can be eliminated. The
clearance of lipophilic compounds is therefore slower than the clearance of water-soluble
compounds.
To become excreted compounds need to be hydrophilic/water-soluble. While to pass membranes
they need to be lipophilic/hydrophobic.
A drug can be excreted without any changes (only for hydrophilic drugs), but for lipophilic drugs
metabolism is needed to make it water-soluble in order to be eliminated.
Chronic use of paracetamol can lead to liver damage already after a few weeks. Toxicity can also be
enhanced by certain things. There also is an antidote.
Metabolism can give rise to reactive metabolites toxicity.
Normal metabolism of paracetamol: Paracetamol is
converted to a compound which is very hydrophilic
and easy to excrete.
Toxic metabolism of paracetamol: Paracetamol is
metabolized to an N-hydroxyl metabolite (generally
unstable molecules) so it changes itself giving rise to
another compound NAPQI (quinone imines are
almost always toxic). They look for electrons
elsewhere and bind giving problems.
Paracetamol is not toxic at low doses because the
route to the hydrophilic compound is much more
faster than the route to the toxic compound the
fast route will be chosen first.
Only when all routes are saturated (so when you take too much) toxicity follows by formation of
quinone imine.
1
,Sometimes metabolites are more toxic than the parent compound toxification or bioactivation.
Sometimes metabolites are less toxic than the parent compound detoxification.
Every drug has desirable and undesirable effects. Off label use = drug is used for a purpose where it
was not developed for (other administration route, other disease, other population). The toxic effect
may be a desirable effect for other diseases.
Whether or not a drug can come to the market, depends on the balance between the desirable and
undesirable effects CBG-EMA-FDA decide these things.
Adverse effect = any unwanted effect of a drug that interferes with the normal function and
adaptability of the body to the environment.
1. On-target toxicity: undesirable effect due to exaggerated pharmacological effect or by
binding to the intended receptor but on another tissue.
How can adverse effects happen? Alcohol, food, too high dose, impaired excretion by kidney
damage or drug-drug interactions; two drugs use the same enzyme slower metabolism of
the drugs,
2. Off-target toxicity: undesirable effect via completely different mechanism (different target)
than the pharmacological effect. The incorrect receptor is activated/inhibited.
Examples:
Liver necrosis due to paracetamol? Off-target. Not the right tissue
Low blood pressure due to beta blocker? On-target.
Cardiotoxicity by anti-histamine terfenadine? Off-target. Completely other receptor is targeted.
Targets for drugs can be:
- Receptors
- Proteins
- Enzymes
- Transporters
- Membrane-lipids
- DNA/RNA (binding can cause tumour formation)
- Ca2+ homeostasis
- Ion channels
- Mitochondria (damage causes cell death by no energy supply)
Immunotoxicity can be due to suppression/stimulation of the immune system. Binding of drug to a
protein can cause heptin formation which induces immune effects.
Toxicity is determined by:
1. Characteristics of the compound: the potency that a drug has an adverse effect. The
potential to be toxic is a hazard. The hazard is determined by chemical and physical
properties of the drug and by the biological effects.
2. Amount/dose/concentration: degree of exposure to the hazard. Exposure is determined by
the dose and systemic exposure and by the exposure of the target organ/tissue/cell.
These two things determine the risks and the safety of the compound.
There are interindividual differences in sensitivity.
Not only the dose but also the rate of dosing determines toxicity. When giving one high dose toxicity
might occur while when giving multiple smaller doses no toxicity occurs.
2
,Toxicity depends not on the dose but on the exposure. The exposure is equal to the AUC of the
concentration-time curve.
Low LD50 means that the compound is toxic. This means that you only need a very small amount of
the compound in order for it to be lethal in 50% of the people.
Risk assessment:
- Does a substance have intrinsic toxic properties and how potent is the substance?
- Are we exposed; via which routes and how?
- Is there systemic exposure?
- Does the substance reach the target in the body?
- Are there relevant species differences?
How to assess the risk of toxicity: first in vitro, then in vivo, then small groups of people (healthy) and
then on patients. This takes 12-24 years. In all phases toxicity is tested.
Research phase: If a compound induces mutations not approved. Drugs which are rapidly
metabolised are also thrown out you should need to administer many times.
In post-marketing surveillance you also look at pharmacovigilance: the detection, evaluation and
prevention of undesirable side effects and interactions.
Most drugs still have side effects when they come to the market. But when the advantages weigh out
the disadvantages you will still provide the drug.
When you test with 1 animal species, you miss about 40% of human toxicities. With 2 animals still
30% of toxicity is not found.
Drugs are not safe by definition. When drugs come to the market the data is limited. The tests in
human are done in particular groups and interactions with other drugs can occur. You will only find
some side effects when they are already on the market.
Lareb: the central collection point for all side effects of pharmaceutical drugs in the Netherlands. It
registers all side effects.
REACH: Registration, Evaluation and Authorization of CHemical substances. Data about safe use of
chemical substances.
Toxicity mechanisms are studied in order to develop antidotes and new drugs, to prevent toxicity, to
cure and to better predict risks for humans.
Lecture 2 Olinga Chapter 5
18/11/2019
Most orally administered drugs enter the body via the small intestine.
Chemical safety is determined by the toxic properties of compound and the exposure to the
compound and its metabolites.
ADME determines the exposure to the final toxic compound.
3
, If there is pre-systemic elimination, the compound is
not toxic because the drug will not come in the
systemic circulation.
Elimination, excretion, detoxication and distribution
away from the target result in a non-toxic effect.
Absorption, reabsorption, toxification and distribution
towards the target result in toxicity.
Toxification and detoxication happen via metabolism.
All blood from the intestines goes to the liver, so that the drugs will be taken up in the liver. The drug
can leave the body by kidney excretion, exhaled air and by the faeces. When drugs are not taken up
at all they will immediately go to the faeces (in an unchanged/not metabolised form).
Toxicity:
1. Local toxicity: drug is not absorbed and only locally toxic. Local toxicity can in the end lead to
systemic toxicity.
2. Systemic toxicity: drug is absorbed and taken up into the general circulation.
Macrophages are activated by local toxicity and can induce cytokine production by systemic
recruitment, which will lead to systemic toxicity.
The bioavailability is a measurement for the exposure of the drug to the body. High bioavailability is
ideal for a drug a lot is absorbed into the systemic circulation. F is decreased by the first pass
effect (metabolism in the intestine and liver). 100% bioavailability no first pass; no metabolism in
the liver or intestines. In case of toxicology you want the bioavailability to be as low as possible,
because then the least toxic effects occur.
Bioavailability = AUCoral/AUCiv
A drug can enter the body via the skin, GI tract, lung and parenteral (im, iv, is).
For oral administration the epithelial cells of the intestinal wall are a barrier for the absorption of a
drug. For rectal/pulmonary/dermal administration also the epithelial cells form a barrier.
Membranes are very lipophilic, so hydrophobic compounds are taken up easily. Hydrophilic
compounds are taken up via transporters.
Passive transport is from high to low concentration. This can be paracellular or transcellular.
Hydrophobic compounds can be taken be transported by paracellular transport and passive diffusion.
There also is carrier-mediated (facilitated) diffusion. This is for more hydrophilic compounds which
can only be transported via a carrier or channel.
Active transport is only possible when there is energy present (ATP). Transport does not have to be
from high to low concentration, the transporter can pump something into the cell against the
concentration gradient. Active transport is always transcellular. This transport is by active
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