Summary METOX

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 drugCompound 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-Hydroxylationcan 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/concentrationdegree 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 levelFirst dose/concentration that gives a significant toxic
effect

NOAEL no observed adverse effect levelThat 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 MDR1multi-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.