Samenvatting
Summary Metabolism and Toxicology lectures
Metabolism and Toxicology
[Meer zien]Voorbeeld 4 van de 53 pagina's
Voorbeeld 4 van de 53 pagina's
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Voorbeeld van de inhoud
MeToxIntroduction
De Graaf
27-11-2020
Metabolism: chemical transformations that compounds undergo in the body (what does the body do
to a compound)
Toxicology: adverse effects of chemicals on the body (what does the compound do to the body)
Fat-soluble compounds stay in the blood by binding to plasma-protein > efficiently absorbed >
clearance is slow. To be excreted > compounds need to become water-soluble.
Metabolism > lipophilic compounds > water-soluble compound > excretion.
Toxification/bioactivation: metabolites are more toxic than parent compound
Detoxification: metabolites less toxic than parent compound.
On-target toxicity: undesirable effect due to exaggerated pharmacological effect (e.g. increased
exposure of the target, interaction with the same target on another cell)
Off-target toxicity: undesirable effect via a completely different mechanism (different target) than
the pharmacological effect.
Normal range = variation in the range of controls
Responder = all above normal range
Hormesis = low concentrations of toxic compound has positive
effect on organ
Measures of toxicity: potential of a compound to be toxic
- LD50 = lethal dose concentration, the dose/concentration to kill half the members tested
- T(oxicity)D50 = dose of a drug necessary get 50% of maximal toxic effect or dose at which
50% of the population shows the toxic effect
- T(oxicity)C50 = plasma concentration to get 50% of toxic effect or plasma concentration to
get 50% of population to get toxic effect
- E(fficacy)D50 = dose of drug necessary to get 50% of desired effect or dose at which 50% of
population show desired effect
- E(fficacy)C50 = plasma concentration of drug necessary to get 50% of desired effect or
plasma concentration of a drug necessary to get 50% of population to get desired effect
LOAEL = lowest observed adverse effect level: first tested dose/concentration that gives a significant
toxic effect.
NOAEL = no observed adverse effect level: dose/concentration just lower than the LOAEL.
Hazard = biological property/potential
Risk = chance on toxicity
,Research phase:
- Screening toxicity
- Screening metabolism
- HTS: high throughput screening
Development phase:
- Toxicity and safety pharmacology
- ADME
- Excretion (in vivo/vitro): 2 test animal species
Clinical phase:
- ‘’non-clinical’’: laboratory animals
- Human pharmacokinetics
- Human toxicity/safety
Post-marketing:
- Side effects
- Pharmacovigilance
- Post marketing surveillance
Adverse drug reactions (ADR):
- Affects 10-20% of hospitalized patients
- 1-5% of hospital admissions are caused by ADR
- 13% of new drugs withdrawn or black box warning because of ADR
Lareb = central collection point for all side effects of pharmaceutical drugs in the NL
REACH:
- Registration, evaluation and authorization of chemical substance
- New European community regulations for substance produced or imported
- Data about safe use
Metox
Mechanisms of toxicity
Salvati
08/12/2020
Why understand the mechanism?
- Change and improve drug
- Understand how to protect from side effect
- Understand how to detoxify
- Understand if mechanisms observed in animals are relevant in humans
4 steps to toxicity:
1. Delivery form site of exposure > target
(absorption, distribution)
2. Reaction of ultimate toxicant with the
target
3. Cellular dysfunction (dysregulation or
alteration of cellular maintenance)
4. Repair vs disrepair or adaptation
Toxicity
,Factors that increase vs factors that decrease delivery of a drug in the body
Detoxication:
- Nucleophiles: conjugation of a functional group > prevents conversion to radicals
- Electrophiles: conjugation with nucleophile
- Fee radicals: SOD and GSH
Reaction of ultimate toxicant with the target:
- Direct interaction
- Adverse alteration of environment: e.g. CO toxicity and carboxyhaemoglobin > CNS and heart
affected
Toxicant and target:
Attributed of target
- Reactive
- Accessible
- Critical function
Reaction types
- Noncovalent binding
- Covalent binding
- Hydrogen abstraction
- Electron transfer
- Enzymatic reaction
Outcomes
- Dysfunction
- Destruction
- Neoantigen formation
Ultimate toxicants: reactive substances
Radicals
- Metabolites of xenobiotics/O2
Electrophiles
- Epoxides
, - Isocyanates
- Ketones
- Acyl halides
- Aromatic amines
- Ester glucuronides
Types of reactions with target: LowMolecularWeight compounds
- Noncovalent binding (reversible): electrostatic/hydrophobic/hydrogen/vdW > influence on
the activity of receptors/enzymes/transporters/etc
- Covalent bond (irreversible): common with electrophilic toxicant that react with nucleophilic
atoms (proteins and DNA/RNA)
- Hydrogen abstraction: e.g. lipids with radicals (peroxidative degradation)
- Election transfer: oxidation/reduction > ROS formation
- Enzymatic reactions
Biologicals reacting with target: proteins, DNA gene therapy, siRNA, antibodies
- Immunological reaction (antigen) and inflammation
- Side effects by receptor binding high species-specific > hard to translate to humans
Attributes of target molecules: reactive, accessible, critical function
- Receptors
- Structural proteins, enzymes, transporters
- Membrane lipids
- DNA/RNA
- Ca2+ homeostasis
- Ion channels
- Mitochondria
Identify a target responsible toxicity:
- Toxicant reacts with it and affect its function
- Toxicant reaches effective concentration at target
- Toxicant alters the target in a way mechanistically related to the observed toxicity
Effect of toxicant on the target
Dysfunction of target:
- Inhibition
- Activation
- Change in tertiary structure
- Disruption homeostasis of the cell
Destruction of target:
- Proteins: degradation by chaperones and ubiquitination
- Lipids: lipid peroxidation
- DNA: fragmentation
Neoantigen formation:
- Immunological reactions and inflammation
Effects depending of target type
Proteins: often to -SH or -NH2 groups
- Impaired function, disturbed homeostasis, many effects, direct and indirect
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