metabolism and toxicology

Question 1

GASHANPP

Answer 1

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)

Question 2

name 4 ways to improve the characteristics of a lead compound or existing drug

Answer 2

1) block metabolism (modify bioavailability
2) improve delivery (optimise bioavailability)
3) pro- drug approach
4) anticipate/ design out toxicity

Question 3

define novelty

Answer 3

a novel drug has chemical structures that has not previously been approved and serve previously unmet clinical need or significantly improve public health

Question 4

what is the outcome of phase I reaction

Answer 4

drug functionalisation, usually oxidation which occurs in the liver

Question 5

what is phase 2 reactions and what is the aim

Answer 5

conjugation reaction with a water soluble group eg sugar to aid urinary or biliary excretion

Question 6

name the 4 types of phase 1 oxidation regulated by P450 enzymes

Answer 6

aromatic hydroxylation, aliphatic hydroxylation, epoxidation, N-Demethylation

Question 7

Other phase 1 reactions (4)

Answer 7

ester hydrolysis, amide hydrolysis, nitro reduction, amine oxidation

Question 8

what is ester hydrolysis regulated by

Answer 8

plasma/ liver esterases

Question 9

what enzymes regulate amide hydrolysis

Answer 9

stomach acid, plasma esterase’s

Question 10

what enzymes regulate nitro reduction

Answer 10

hepatic reductases. intermediates are reactive and can be very toxic

Question 11

what enzyme regulates amine oxidation

Answer 11

monoamine oxidase

Question 12

what is the most common phase 2 reaction

Answer 12

glucoronidation

Question 13

what are the 3 types of phase 2 reaction

Answer 13

glucuronidation, sulphate conjugation, conjugation of aromatic carboxylic acids with glycine

Question 14

why do you need to be careful not to block any hydrogen binding sites

Answer 14

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

Question 15

4 ways in which toxicity is predicted

Answer 15

COMB- consideration of structural alerts, Off target in silico screening, metabolomics, binding assays

Question 16

why can planar drugs be toxic

Answer 16

planar- can form adducts and interact with DNA, damaging it

lots of benzene rings, no bonds allowing it to rotate, they are mutagens

Question 17

what is a mutagen

Answer 17

any substances that causes mutations in DNA

Question 18

how to make a drug less planar

Answer 18

add large groups to repulse the benzene ring eg methyl groups. make it more bulky –> to cause rotation

Question 19

list all the structural alerts

Answer 19

nitroromatics, anilines, quinones, alkyl halides, michael acceptors, carboxylic acids

Question 20

what are nitroaromatics metabolised to

Answer 20

nitroso

Question 21

what are anilines metabolised to

Answer 21

nitroso

Question 22

what are quinones metabolised

Answer 22

toxic species, very reactive to nucleophiles

Question 23

what are alkyl halides metabolised to

Answer 23

inherently reactive with nucleophiles

Question 24

what are michael acceptors metabolised to

Answer 24

inherently reactive with nucleophiles

Question 25

what are carboxylic acids metabolised to

Answer 25

metabolised to acyl glucuronides

Question 26

do structural alerts mean a drug cannot be licensed

Answer 26

no it can just flag potential problems

Question 27

explain mechanism of paracetamol overdose

Answer 27

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

Question 28

why can carboxylic acids be toxic

Answer 28

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

Question 29

what is IDT (idiosyncratic drug toxicity)

Answer 29

often blamed on carboxylic groups, a drug toxicity reaction that unexpected or explained

Question 30

2 most common ways of blocking drug metabolism

Answer 30

drug fluorination and drug chlorination

Question 31

describe why drugs are fluorinated

Answer 31

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

Question 32

what does drug chlorination do

Answer 32

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

Question 33

what is another advantage of doing drug fluorination or chlorination

Answer 33

generates a novel compound which is potentially patentable

Question 34

what is one risk of blocking metabolism too much

Answer 34

it’ll build up in the body too much

Question 35

define bioisosteres

Answer 35

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.

Question 36

can bioisosteres modify a drugs biological property

Answer 36

potentially eg metabolism

Question 37

name an example of a bio isostere of a nitro aromatic

Answer 37

CF3, CN, lactone

Question 38

name bioisosteres of an aromatic amine (NH2 attached to a benzene)

Answer 38

CH3, OH attached to a benzene

Question 39

name 2 bioisosteres of carboxylic acids

Answer 39

tetrazole and 2,6-Diflurorphenol

Question 40

which is the better bioisostere of carboxylic acid out of tetrazole and 2,6-Difluorophenol and why

Answer 40

tetrazole as it mimics acidity