Inter-species + Inter-individual Differences Flashcards
What is included in pre-clinical toxicity screening
Mutagenicity
Carcinogenicity
Reproductive toxicity
Acute toxicity
Subchronic toxicity
Chronic toxicity
Describe the use of rodents in toxicology studies
Usually rats as they’re standardised
Mice can be genetically manipulated and organ systems are more reproducible
-> guinea pigs better
Describe the use of non-rodents in toxicology studies
Not commonly used anymore
Dogs usually used to test cardiovascular effects
Mini-pigs have a similar cardiovascular system to humans
Rabbits have a similar reproductive cycle so are used in reproductive toxicity
When would primates be used in toxicity studies
Used to study CNS effects due to their similar CNS
Antibody therapy as their immune system is most similar to humans
How could the toxicological effect of long term administration be monitored
6-12 month toxicological studies in rodents and non-rodents
How can a chemical be tested for it carcinogenicity
Lifetime exposure in rats and/or mice
How can the complete metabolic fate of a chemical be monitored
Characterisation of the complete metabolic profile often using radiolabelling
Shows if the active metabolites contribute to efficacy or toxicity
How can potential chemical interactions be excluded based on previous knowledge
Identification of metabolising enzymes responsible for the new chemical metabolism
In vitro chemical interaction studies using humane enzymes
Descirbe the ideal animal model
Replicates the human metabolism of the chemical
Share the same molecular pathways and enzymes
Should be a good model for a given human disease
What are the factors affect drug metabolism in lab animals
Lab animals are in a controlled environment and lack genetic diversity
Limited effects of sex differences
= controlled and stable metabolism
What are the factors affect drug metabolism in the human population
High levels of genetic diversity
Environmental and lifestyle pressures
Impact of sexdifferences
= No control and variable metabolism
What variation in metabolism is there between species
Difference in proportion, specificity and distribution of phase I and phase II enzymes
Different in mechanisms regulating phase I and phase II enzyme expression
Difference in responses to DNA damage between animals and humans
What variation in metabolism is there between humans
Population diversity: SNP’s, age, body fat, gender and health status
Extreme conditions
Exposure
Describe the difference in CYP450 distribution between human and rat livers
Might see CYPS in rats that we don’t see in human e.g CYP2C11
Different levels of CYPS: higher levels of CYP1A2 and 2E1 in humans that rats
= might not see some toxic effects in rats but in humans
What are the advantages and disadvantages of testing toxicity in lab animals
Adv: helps deduces the mechanism of toxicity
Dis: limited experimental approach that implies they share the same metabolic pathway
What chemical is a good example of the difference in drug metabolism in humans vs rats
Nicotine
In humans metabolised by CYP2A6 which is highly expressed and a SNP causes nicotine dependence
But in rats nicotine is metabolised by CYP2B
How does phase II metabolism vary between species
Promotion of phenol conjugated to glucuronides and sulfates
Can lead to significant variation in metabolism between species
How do gender differences effect CYP450 levels in humans and rodents
Humans: no major differences
Rodents: CYP3A, 2A, 2B and 2C higher in males than females
How do inter-species differences effect hydrolysis of esters in humans vs rodents
Higher level of cholinesterases in humans than rodents
Higher level of carboxylesterases in rodents than in humans
How does age affect metabolism in humans
Long life span
Children: many changes to P450s in the first 4 years of life
Adults: specific activity does not decrease with age
Elderly: reduced liver size and liver blood flow = reduced clearance by metabolism
How does age effect metabolism in rodents
Limitations for long-term exposure
Have short life span of approx 2 years
Have ‘mature’ P450s at 6 weeks = difficult to study toxicology in children
What is the difference in biliary excretion between species
Cut off point in terms of MC for biliary vs renal excretion
Might be due to differences in specificity for ABCC2 transporter
Describe how genetic differences between DA rats have an effect on their ability to reduce high blood pressure
Female DA lacks CYP2D1 = can’t hydroxylate debrisoquine
Male DA express a male specific CYP2D isoform = can hyroxylate debrisoquine
What is a good model to study debrisoquine toxicity for CYP2D6 ‘poor metabolisers’
Female DA
