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Summary METOX
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A summary for the course metabolism and toxicology
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Metabolism and Toxiclogy (MeTox)Day 1 introduction – de Graaf
- Metabolism chemical transformation that compounds undergo
o What the body does to the compound?
- Toxicology adverse effects of chemicals on organisms
o What does the compound to the body?
Paracetamol
- Safe pain killer max 6 per day 3 g
- Deadly dose is 30 g
- Water-soluble compound is inefficiently absorbed and easily excreted
- Fat-soluble, Lipophilic compound needs to be absorbed
o Lipophilic compound is efficiently absorbed, binds to proteins in the blood and clearance
therefore is slow!
o Its metabolized and excreted from the blood
- Compounds need to pass membranes and need to be lipophilic but to become excreted, they
need to be hydrophilic
Drugs are often lipophilic can pass the membrane
Oral drug usually not hydrophilic hard to pass the membrane
- Hydrophilic drug can be easily excreted again short half-life
- Paracetamol lipophilic once its taken up difficult to get rid off
o Can bind plasma proteins plasma protein like albumin can’t pass kidney
o Clearance is slow
- For compounds to be excreted they need to be hydrophilic
Metabolism transforms a lipophilic compound into a water-soluble compound that can be excreted
The faith of pharmaceuticals in our body:
- Take a drugCompound absorbed uptake in the blood
- Distribution distribution in the body to organs and tissues after systemic uptake
- Metabolism transformation to other compounds
- Excretion in urine or faeces
Paracetamol metabolized has a hydroxyl group used to couple a polar compound (Sulfate, ST or
gluconate, GT) make it water soluble easy to be excreted in the kidneys via the urine
- Take a lot of paracetamol routes become saturated
- N-Hydroxylationcan auto hydroxylase into NAPQI (electrophilic compounds) can bind a
nucleophilic compound (proteins, DNA, RNA) forms an adduct cell damage, cell death
- GSH-T safe route Glutathione nucleophilic detoxifies NAPQI
,Sometimes metabolites are more toxic that parent compound toxification, bioactivation NAPQi
route
Sometimes less toxic detoxification GSH-T route
Interaction of xenobiotic
- Every drug has desirable and undesirable effects (toxic effect)
o Toxic effect can be used sometimes
Adverse effect
- Any (unwanted) effect of a drug that interferes with the normal function and adaptability of the
body to (stimuli from) the environment.
- Due interaction with a target
o Receptor
o Other proteins: enzymes, enzymes etc.
o Membrane-lipids
o DNA/RNA
o Ca2+ homeostasis
o Ion channels
o Mitochondria
Adverse reaction
- Local or systemic
- Rapid onset/acute or delayed/chronic
- Reversible (take away the stimulus) or irreversible
- Gradual or all-or-nothing (formation of tumor or death)
- Direct or indirect
Adverse reaction leads to adverse effects
Immunotoxicity
- Toxic effects mediated by the immune system: immunological response to damage somewhere in
the body, e.g. sensitization, hapten formation
Undesirable effects: on-target and off-target
- On-target undesirable due to exaggerated pharmacological effect overexposed of a certain
drug interactions with the same target on/in another cell/organ
- Off-target toxic effect by different mechanism than the pharmacological effect
On-target can be on intended tissue or unintended tissue
Off-target the same
Off-target or on-target
- Liver necrosis off-target on unintended tissue
,- Myotoxicity on-target on unintended tissue, work on the liver normally same
pharmacological effect in muscle
- Beta blocker on-target intended tissue
- Cardiotoxicity by anti-histamine drug off-target in the unintended tissue
Toxicity and dose
- Often toxicity is due to the dose
- Dose effect curve
- Dose response curve shows percentage of animal reacting
Hormesis
- Effect of vitamin A on embryo development
- Both deficiency and overdose give toxicity
Same dose does not correspond to the same exposure
- Exposure actual concentration at the target
- Toxic effect depends on concentration at target related to the dose but also:
o Differences in exposure routes
o Species differences in ADME
o Accumulation
o Time (dose x time) Interactions
Exposure makes it toxic
- Some compounds are more potent than others
- Toxicity is determined by
o Characteristic of the compound danger/hazard potential of adverse effects
o Amount/dose/concentrationdegree of exposure to hazard
- Both characteristic determine the risk and safety
Toxicity/safety is determined by
1. Characteristics of the compound
2. The amount/dose/concentration degree of exposure to hazard
- Chemical and physical properties
- Biological effects
- Dose and systemic exposure
- Exposure of the target organ/tissue/cell
Measure of toxicity
- LD50, TC50 or EC50
- TD50= dose of drug necessary to provoke 50% of the maximal toxic effect or the dose at which 50%
of the exposed population shows the toxic effect
- TC50= concentration of drug to provoke 50% of the maximal toxic effect or the plasma
concentration necessary to provoke the toxic effect in 50% of the population
, - ED50= dose of a drug needed to achieve 50% of desired effect
o Or dose at which 50 % of population shows desired effect
- EC50= “” “” but with plasma concentrations instead of dose
LOAEL Lowest observed adverse effect levelFirst dose/concentration that gives a significant toxic
effect
NOAEL no observed adverse effect levelThat dose/concentration that is just lower than LOAEL
Neurotoxicity on brain cells in vitro was found of a new drug
Hazard anything that can cause harm
Risk chance that someone will be harmed by the hazard
Risk safety assessment
- LOAEL first significant effect
- NOAEL just below the LOAEL
ADI acceptable daily intake reflect the risk
TI therapeutic index TD50/ED50
MOS margin of safety TD1/ED99
- Nowadays not the toxic dose is used but the concentration TC1/EC99
TI vs MOS
3 important fields of toxicology for risk assessment
- Regulatory toxicology
- Risk assessment
- Descriptive toxicology
Drug research: testing and predicting
Day 2 Toxicokinetics and ADME –
Olinga
P-gp efflux transporter MDR1multi-drug-resistant
Free drug will pass the membrane also non-
charged
When a medication is administered via routes
other than intravenous, its bioavailability is
generally lower than that of intravenous due to
intestinal endothelium absorption and first-
pass metabolism by the liver.
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