metabolism and toxicology Flashcards
GASHANPP
good binding interactions. acceptable bioavailability, side effect profile, high receptor affinity and selectivity, active in animal models, novel, pharmaceutics eg water solubility and pharmacokinetics (ADME)
name 4 ways to improve the characteristics of a lead compound or existing drug
1) block metabolism (modify bioavailability
2) improve delivery (optimise bioavailability)
3) pro- drug approach
4) anticipate/ design out toxicity
define novelty
a novel drug has chemical structures that has not previously been approved and serve previously unmet clinical need or significantly improve public health
what is the outcome of phase I reaction
drug functionalisation, usually oxidation which occurs in the liver
what is phase 2 reactions and what is the aim
conjugation reaction with a water soluble group eg sugar to aid urinary or biliary excretion
name the 4 types of phase 1 oxidation regulated by P450 enzymes
aromatic hydroxylation, aliphatic hydroxylation, epoxidation, N-Demethylation
Other phase 1 reactions (4)
ester hydrolysis, amide hydrolysis, nitro reduction, amine oxidation
what is ester hydrolysis regulated by
plasma/ liver esterases
what enzymes regulate amide hydrolysis
stomach acid, plasma esterase’s
what enzymes regulate nitro reduction
hepatic reductases. intermediates are reactive and can be very toxic
what enzyme regulates amine oxidation
monoamine oxidase
what is the most common phase 2 reaction
glucoronidation
what are the 3 types of phase 2 reaction
glucuronidation, sulphate conjugation, conjugation of aromatic carboxylic acids with glycine
why do you need to be careful not to block any hydrogen binding sites
as this may cause the drug to build up. you need the binding sites free for binding with glycine so it can be excreted better
4 ways in which toxicity is predicted
COMB- consideration of structural alerts, Off target in silico screening, metabolomics, binding assays
why can planar drugs be toxic
planar- can form adducts and interact with DNA, damaging it
lots of benzene rings, no bonds allowing it to rotate, they are mutagens
what is a mutagen
any substances that causes mutations in DNA
how to make a drug less planar
add large groups to repulse the benzene ring eg methyl groups. make it more bulky –> to cause rotation
list all the structural alerts
nitroromatics, anilines, quinones, alkyl halides, michael acceptors, carboxylic acids
what are nitroaromatics metabolised to
nitroso
what are anilines metabolised to
nitroso
what are quinones metabolised
toxic species, very reactive to nucleophiles
what are alkyl halides metabolised to
inherently reactive with nucleophiles
what are michael acceptors metabolised to
inherently reactive with nucleophiles
what are carboxylic acids metabolised to
metabolised to acyl glucuronides
do structural alerts mean a drug cannot be licensed
no it can just flag potential problems
explain mechanism of paracetamol overdose
15% of paracetamol is metabolised to a quinone intermediate, normally this is detoxified by glutathione but in overdose quinone accumulates and reacts with any nucleophile which leads to fatal liver damage
why can carboxylic acids be toxic
because they undergo glucuronidation to form acyl glucuronides, these can undergo ester hydrolysis and the glucuronic acid irreversibly transfers to proteins and nucleic acids, preventing them from carrying out their function
what is IDT (idiosyncratic drug toxicity)
often blamed on carboxylic groups, a drug toxicity reaction that unexpected or explained
2 most common ways of blocking drug metabolism
drug fluorination and drug chlorination
describe why drugs are fluorinated
fluorine is a good bio-isostere of hydrogen as it is the same shape and size. H doesn’t change shape or appearance of drug. the C-F bond is stronger then C-H bond and cannot be easily broken
what does drug chlorination do
block metabolism of methyl group. Chlorine is a larger group- good mimic of a CH3 group. The Cl atom does not contain CH bonds and cannot be oxidised
what is another advantage of doing drug fluorination or chlorination
generates a novel compound which is potentially patentable
what is one risk of blocking metabolism too much
it’ll build up in the body too much
define bioisosteres
A bioisostere is a molecule resulting from the exchange of an atom or of a group of atoms with an alternative, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new molecule with similar biological properties to the parent compound.
can bioisosteres modify a drugs biological property
potentially eg metabolism
name an example of a bio isostere of a nitro aromatic
CF3, CN, lactone
name bioisosteres of an aromatic amine (NH2 attached to a benzene)
CH3, OH attached to a benzene
name 2 bioisosteres of carboxylic acids
tetrazole and 2,6-Diflurorphenol
which is the better bioisostere of carboxylic acid out of tetrazole and 2,6-Difluorophenol and why
tetrazole as it mimics acidity
