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C2 > Toxicology🦠 > Flashcards

Toxicology🦠 Flashcards

1
Q

What are 4 key strategies used to look for new drugs?

A
  • follow-on compounds
  • computational modelling + sequencing
  • serendipitous discovery
  • evergreening
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2
Q

What are follow-on compounds?

example?

A
  • a drug originally discovered for one purpose, but found to be incredibly effective for another purpose
  • e.g. sildenafil originally for CV issues, now treats erectile dysfunction
  • i.e. luck method
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3
Q

What kinds of drugs are produced from serendipitous discovery?

A
  • structurally similar to previously reported drug

- AKA “fast followers” or “me too” drugs

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4
Q

serendipitous discovery drugs have same mechanism as which?

2 examples?

A
  • Same mechanism as the prototype drug but different enough to be considered novel
  • e.g. captopril, enalapril
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5
Q

Why are drugs found by serendipitous discovery appreciated by regulators?

A
  • provide professionals & patients with multiple options

- contribute to keeping prices low

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6
Q

What kind of drugs are discovered through evergreening?

A
  • Extreme form of a “me too” drug

- Practically extending the duration of a patent with minimal chemical intervention or changes

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7
Q

computational modelling + sequencing: name of project used and what does the process achieve/entail?

A

human genome project

increasing num of solved protein x-ray crystal structures

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8
Q

whens computational modelling + sequencing ideal/used?

A

when step 1: follow on compounds from natural drug doesnt work to get lucky

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9
Q

computational modelling and sequencing requires understanding of what?

A

the target!

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10
Q

How does esomeprazole relate to omeprazole, and how was it discovered? (3)

A
  • pure enantiomer of omeprazole where alcohol points forwards
  • discovered through evergreening
  • improved properties: PK profile, resistance to metabolism, conductive to a longer duration
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11
Q

Process to find new drugs

Where do we start when discovering new drugs? (hint: t_ v_, h_ i_)

A

target validation: explore relationship between pharmac.l modulation of a target and pathological condition. Correlation is not enough… causality must be established

hit identification: chemically accessible (synthesised easily) compound displaying initial activity towards target; can be done individually in lab

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12
Q

What are the characteristics the of the ‘hits’ identified?

affinity? MW? cLogP? number of rings? HBAs? HBDs?

A
  • moderate affinity (nM - µM)
  • low MW (150 < 400)
  • cLog P < 4.5
  • 1-4 rings
  • <8 HBA
  • <5 HBD
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13
Q

where to look for new drugs? 3 designs

A

rational design
high throughput screening
natural products

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14
Q

What type of design is where we look to find hits?

A

rational design

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15
Q

whats rational design based on and what does it utilise?

A
  • can be based on physiological binders (substrates, co-factors)
  • starts w molecule known to be active, attempts to improve on it
  • Generally utilises structural information to improve ligand interactions in binding site
  • attempts to improve what we can do at binding site using structural information
  • e.g. protein kinases are target, so develop sunitinib similar to ATP, its substrate
    and Ad -> propanolol
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16
Q

Instead of rational design, what could you use when you don’t know much about your target?

A

high-throughput screening - screening as many compounds as possible and hope to get lucky

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17
Q

What are 2 types of screens used in high throughput screening?

A
  • unselected screens

- selected (directed) screens

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18
Q

What are the disadvantages of using unselected screens in high-throughput screening?

A

• Hit rates likely to be ~ 1%
• need to screen millions of compounds -> decent num of hit families to follow up
• Limited by budget, time, resources and intrinsic throughput:
limited to a number of compounds at a single concentration; generates noise

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19
Q

What are selected (directed screens) used in high-throughput screening?

A
  • sometimes enough info about target to inform screening

- combo of rational design and unselected screening

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20
Q

What are the advantages of selected (directed) screens?

A
  • faster
  • reduces costs
  • easier identification of true activity
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21
Q

high throughput screening:
2. selected (directed) screens

num of compounds large -> small

gradual scale

A 
diversity based
property based
(rational design):
target class/ privileged strucs
pharmacophore based libraries
target specific libraries
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22
Q

What are natural products?

3 examples

A
  • also looked at for when discovering new drugs
  • chemicals produced by organisms (commonly fungi, bacteria, plants)
  • e.g. salicylic acid, geldanamycin, paclitaxel (Taxol)
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23
Q

Why are natural products difficult to synthesise?

A
  • they are often very complex structures, with multiple stereocentres and macrocycles
  • this makes it difficult to control the synthesis
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24
Q

What are PAINs?

A

Pan-Assay Interference Compounds:

  • Positive hit compounds which turned out to be due to non-specific binding (artefacts)
  • false positives (e.g. quinones)
  • Compounds consistently identified as promising hits against different proteins
  • Defined structures, covering several chemical classes
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25
Q

Why are PAINs problematic?

A

Time and research money wasted, none could be progressed further

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26
Q

Fragment screening:

What is the rule of 3 (RO3) in regards to lead-like compounds?

A

it describes the key attributes of a lead-like compound:

  • Log P < 3
  • MW <300 Da
  • No more than 3 HBAs
  • No more than 3 HBDs
  • No more than 3 rotatable bonds
  • recent extension: polar surface area less than or equal to 60 Angstroms (Ų)
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27
Q

What is fragment screening?

A

A method of reducing ligand complexity to increase the chance of a match with target site

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28
Q

What are the advantages of fragment screening? (3)

A
  • delivers highly effective chemical diversity from smaller libraries
  • can sample chemical space at finer resolution
  • fragments can bind targets in multiple ways (though usually with relatively weak affinity for the target)
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29
Q

Describe the process of fragment screening (4)

A

1) start with initial library of mismatched fragments which are chemically diverse and SCREEN them
2) identify low affinity hits; ideal dissociation constant/ binding affinity will be in millimolar/high micromolar range
3) OPTIMISE strucs to generate a higher affinity compound
4) FURTEHR OPTIMISE until dissociation constant is in nanomolar range

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30
Q

Fragment Screening case study: 7-azaindole

A
  • Target: mutated form of the kinase B-RAF (V600E) which is present in ~50% of melanomas
  • Library of 20’000 fragments (150-350 Da) screened at fixed conc 200 µM → 238 hit fragments
  • Further characterised through protein-inhibitor co-crystallography to ensure for selective binding
  • 7-azaindole group consistently led to high binding affinity for active site
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31
Q

When is a compound likely to be produced by rational design?

A

any molecules that look like enzyme substrates/macromolecules:

  • proteins: a peptide-like structure with amino acid residues, amine bonds
  • sugars: carb like structure (6-membered cyclic ethers at centre of molecule with a lot of O atoms)
  • nucleic acids: adenine, sugar and phosphate group
  • rotatable bonds
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32
Q

When is a compound likely to be produced by a high throughput screen?

A

flat: few rotatable bonds and high number of sp2 centres

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33
Q

When is a compound likely to be a natural product?

A
  • lots of stereocentres/rotatable bonds

- complex structure

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34
Q

Pan-assay interference compounds are what?

and what are positives from non-specific binding called?

A

false-positive hit compounds

artefacts

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35
Q

The first stage of turning a hit into a drug is ?

A

The first stage of turning a hit into a drug is hit-2-lead

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36
Q

What are 4 meaningful prerequisites before starting an optimisation campaign?

A
  • structure must be chemically acceptable
  • hit must respond to chemical modulation to generate quantifiable SARs
  • need freedom to operate
  • favourable ADME profile
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37
Q

What is meant by a hit needing to be chemically acceptable?

A

the reaction needs to be able to be performed large scale

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38
Q

What is meant by a hit needing to respond to chemical modulation and therefore generating a quantifiable structure activity relationship?

A

need to be able to change + manipulate (chemically modulate) structure to generate quantifiable structure-activity relationships

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39
Q

What is meant by a hit needing freedom to oeprate?

A

in terms of intellectual property, the drug needs to be marketable

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40
Q

When does the ADME profile of a hit become clear?

A

when cross-referenced with toxicology

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41
Q

Once a suitable hit is identified, optimisation occurs across multiple what? Why is the problematic? (3)

A

multiple dimensions

= means multiple parameters need to be optimised all at once

  • end up with a trade-off to strike a balance among multiple conflicting priorities
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42
Q

What percentage of drug candidates entering clinical trials become marketed products?

A

10%

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43
Q

What ADME process does the low water-solubility of a compound limit?

A

absorption, as the compound needs to dissolve and be in solution before it can be absorbed

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44
Q

When optimising a compound’s ability to cross the blood brain barrier, what can we modulate?

Example: difference between hydroxyzine and cetirizine

A

pKa (hence the functional groups)

  • cetirizine has the free OH group in hydroxyzine changed to COOH, changing the compound’s pKa and hence preventing it from crossing the BBB as pKa decreased from 15 to 5-10?
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45
Q

lead optimisation: affect of changing free OH (primary) to COOH?
hydroxyzine -> cetirizine

A

pka goes from 15 to 5-10.

can no longer cross BBB

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46
Q

Example of imatinib and how changing its structure improved its pharmacokinetics

  • amide
  • methyl
  • extra R group
A
  • adding amide enhanced selectivity
  • methyl group increases selectivity by eliminating protein kinase C activity
  • extra R group increases sol and oral availability
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47
Q

4 possible strategies used to make changes to a compound to optimise it?

A

homologation
disjunction
conformational constraining
bioisostere substitution

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48
Q

What is a homologous series?

A

Series of compounds that differ by a constant unit e.g. CH2

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49
Q

How do we use homologation to optimise a lead?

what does it help us identify?

A
  • identify structure-activity relationships (SARs) for the particular position of substitution
  • e.g. the highest affinity compound has a medium chain length in example

can be affinity/selectivity/ solubility/ half life

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50
Q

describe the second strategy (d…) we use to determine what changes to make to a compound to optimise it?

A

disjunction:

  • identify minimal structure associated with activity at the sought target and remove the rest
  • hence working backwards from something complex to find out what the important section is
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51
Q

What is the aim of disjunction?

A
  • simplify synthesis

- ‘engineer-out’ activities at unwanted targets and hence rid of side-effects

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52
Q

Example of disjunction: morphine

A
  • begin w complex structure
  • in 1st step, rid of 5-membered O ring as well as some OH groups as they’re not needed - loss of stereochemistry
  • we still need some kind of substituent for R2 and R3
  • rid of ring as it’s not important, then rid of hydroxy group and replace X with heteroatom
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53
Q

What is the third strategy (c… c…) we use to determine what changes to make to a compound to optimise it?

what model does it use?

A

conformational constraining:

  • freeze drug in a particular conformation (shape in space) to best suit the target)
  • uses the lock and key model concept
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54
Q

Conformational constraining is used in molecules with what type of bonds?

A

rotatable, as these molecules are flexible and can adopt multiple conformations; we need a fixed shape that best interacts with the target

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55
Q

In conformational constraining, what is the ideal conformation called?
how can it be determined?

A

bioactive conformation

determined: trial and error/ rational

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56
Q

What is one way of identifying the ideal conformation in conformational constraining?

A

rational design - look at the crystal structures of proteins we’re targeting

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57
Q

2 ways conformational constraining can be acheived?

A

using substituents and or struc changes

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58
Q

Example of conformational constraining: atenolol, levcromakalim

A
  • atenolol: no bonds restricted which can rotate a lot in space
  • levcromakalim: more potent due to the completion of the cyclic ring, constraining a lot of stereochemistry - the OH will always point upwards
    now fixed in space
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59
Q

What is the fourth strategy (b… s…) we use to determine what changes to make to a compound to optimise it?

A

bioisostere substitution:

  • replace substituents with bioisosteres - have chemical/physical similarities to that it replaces
  • results in production of similar biological properties
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60
Q

bioisostere modifications will depend on role of moieties they replaced, what 4 things can be changed/affected?

A

structural
receptor interaction
PK
metabolism

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61
Q

What properties of a compound will be affected if a bioisostere replaces a STRUCTURAL substituent? (5)

A
  • geometry
  • size
  • shape
  • polarizability
  • hydrogen bonding
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62
Q

What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in RECEPTOR INTERACTION?

A

all parameters

except lipid/water solubility

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63
Q

What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in PHARMACOKINETICS? (3)

A
  • lipophilicity
  • pKa
  • H bonding
64
Q

What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in METABOLISM?

A

metabolic reactivity: reactive metabolites may be important for efficacy

65
Q

Example of bioisostere substitution: losartan

A
  • carboxylic acid replaced with tetrazole (N type ring)

- same acidic pKa kept as wanted, but lipophilicity increased

66
Q

how can tetrazoles act as bioisostere for carboxylates?

A

because have similar pKa :D

67
Q

Example of bioisostere substitution: soterenol

A
  • OH group replaced with sulphonamide at meta position!
  • improves metabolic profile but keeps pKa same
  • therefore weak acidity of substituent in meta position is maintained
68
Q

as a conformational straining lead modification, what may added to structure to decrease rotation/fitting into diff sites?

A

bulky constituents (rings)

69
Q

what 6 systems does drug toxicity affect?

A 
cardiovasc
nervous
hepatic
rep
GI
renal
70
Q

What are cardiovascular examples of drug toxicity? 3

A
  • blood pressure changes
  • effects on cardiac rhythm
  • thrombosis
71
Q

What are respiratory examples of drug toxicity? (3)

A
  • respiratory suppression
  • respiratory constriction
  • respiratory inflammation
72
Q

What are nervous system examples of drug toxicity? (2)

A
  • seizures

- suicide

73
Q

What is a hepatic example of drug toxicity?

A

drug-induced liver injury (DILI)

74
Q

What are gastrointestinal examples of drug toxicity? (2)

A
  • bleeding diarrhoea

- motility effects

75
Q

What is a renal example of drug toxicity?

A

drug induced renal injury (DIRI)

76
Q

What are 5 causes of drug toxicity?

A
  • target driven
  • idiosyncratic toxicity
  • drug interactions
  • carcinogenicity
  • generation of reactive metabolites
77
Q

What is the concept of secondary pharmacology?

A
  • human body contains >20,000 proteins and other macromolecules
  • therefore drugs are likely to bind to more than one target
  • a biological target/effect not linked to drug’s efficacy
78
Q

Gibbs free energy diagram of a protein and ligand interacting

A

unbound P+L

↑

P+L solvated ↓

                        P+L complex
79
Q

What does the magnitude of ΔG in the Gibbs free energy diagram of a protein and ligand interaction define?

A

the strength of the interaction

80
Q

What unfavourable enthalpic processes lead to us from getting from the solvated protein and ligand up to the unbound protein and ligand?

A
  • loss of ligand-water bonding interactions

- loss of protein-water bonding interactions

81
Q

What unfavourable entropic processes lead to us from getting from the solvated protein and ligand up to the unbound protein and ligand?

A
  • loss of conformational flexibility in protein

- loss of conformational flexibility in ligand

82
Q

Is it enthalpically favourable to lose ligand or protein-water bonding?

A

no, as it results in gaining energy

83
Q

What favourable enthalpic (energy out) processes lead to going from unbound ligand/protein ↓ to a protein-ligand complex?

A
  • formation of bonding interactions

- energetic changes in protein or ligand

84
Q

What entropic processes lead to going from unbound ligand/protein ↓ to a protein-ligand complex?

A
  • desolvation of ligands

- return of bound water to bulk state

85
Q

What enthalpic process that increases energy is important for hydrophilic drugs?

A

loss of ligand-water bonding interactions, as the hydrophilic drug wanted the water

86
Q

What enthalpic process that decreases energy is important for hydrophilic drugs?

A

formation of bonding interactions w protein which is favourable

87
Q

What enthalpic processes that increase energy are important for lipophilic drugs?
(opposite to hydrophilic!)

A
  • loss of protein-water interactions (didn’t want water in first place)
  • energetic changes in protein/ligand
88
Q

What entropic processes that increase energy are important for lipophilic drugs?

A
  • loss of conformational flexibility in protein

- loss of conformational flexibility in ligand

89
Q

What enthalpic process that decreases energy is important for lipophilic drugs?

A

energetic changes in the protein or ligand

90
Q

What entropic processes that decrease energy are important for lipophilic drugs?

A
  • desolvation of ligands

- return of water to the bulk state

91
Q

Hydrophilic drugs bind predominantly through what?

A

bonding interactions

  • high requirement for interactions to be optimal for target
  • need to pay price of breaking interactions w water
92
Q

Lipophilic drugs bind predominantly through what?

A

entropic effects:

  • pushed out by water into an environment less unfavourable
  • this results in interaction that may be much less specific, but still needs to fit the binding site
93
Q

Example of secondary pharmacology: NSAIDs

A
  • inhibit COX enzymes to prevent prostaglandin synthesis
  • COX-2 inhibition= therapeutic anti-inflammatory effect
  • COX-1 inhibition affects gastric lining = secondary pharmacology
  • increased risk of cardiovascular side effects linked to COX inhibition
94
Q

why try to make COX2-selective drugs specifically?

A

COX1 inhib -> ulceration, gastric lining
but
COX2 inhib -> anti-inflamm effects

95
Q

secondary pharmacology is driven by (2)?

A

enthalpy and entropic effects

96
Q

What are the two types of biotransformation (metabolism)?

A

phase I and phase II

97
Q

What are the 3 main mechanisms of phase I metabolism?

A
  • oxidation
  • reduction
  • hydrolysis
98
Q

What oxidation reactions occur in phase I metabolism? (h… o… d…)

A

hydroxylation:

  • aliphatic
  • aromatic

oxidation:

  • N-oxidation
  • S-oxidation

dealkylation:

  • N-dealkylation
  • S-dealkylation
  • O-dealkylation
99
Q

example of Phase 1: oxidation: aliphatic hydroxylation?

A

adding OH to chain coming off benzene ring

100
Q

example of aromatic hydroxylation?

A

adding OH onto benzene ring- para position (opposite)

101
Q

whats N-oxidation?

A

adding O- onto N = N+

102
Q

whats S-oxidation (sulfonation)?

A

R - S -> R - S = O
I I
R R

adding O

103
Q

Example of N-dealkylation

A

removing alkyl group from N:

  • N - CH3 -> -N - H
104
Q

Example of S-dealkylation

A

removing alkyl group from S:

  • S - CH3 -> - S - H
105
Q

Example of O-dealkylation

A

removing alkyl group/s from O:

  • O - CH3 -> - O - H

or
- O - C2H5 -> - O - H

106
Q

In reduction reactions in phase I metabolism,
what two groups could a nitro group be reduced to?
What is a carbonyl reduced to?

A
  • nitro group → hydroxylamine
  • nitro group → amine
  • carbonyl → alcohol
107
Q

In hydrolysis reactions in phase I metabolism, what are esters, amides or phosphates be reduced to?
What is hydrazide reduced to?

A
  • ester/amide/phosphate → corresponding acid and alcohol

- hydrazide → acid and substituted hydrazine

108
Q

What is the main class of proteins involved in phase I metabolism?

A

Cytochrome P450s, account for ~60% of commonly prescribed drugs

109
Q

Where does the main class of proteins catalysing phase I metabolisms carry out oxidations?

A

in liver cells

110
Q

How many isoforms of CYP450s are known in man?

A

> 100, some are synthetic e.g. hormone biosynthesis

111
Q

What determines the rate of oxidation by cytochrome P450s?

A
  • stereoelectronics: what’s occurring with the bonds? how available are electrons to form/break bonds?
  • concentrations: of products

drug ⇌ drug-CYP complex -> Metabolite-CYP complex ⇌ Metabolite

112
Q

What is the constant for the equilibrium between the drug and drug-CYP450 complex?

drug ⇌ drug-CYP complex -> Metabolite-CYP complex ⇌ Metabolite

A

Kd = dissociation constant - binding affinity between protein and drug

      Kd drug  ⇌  Drug-CYP complex
113
Q

What is the constant for the equilibrium between the drug-CYP450 complex and metabolite-CYP complex?

drug ⇌ drug-CYP complex -> Metabolite-CYP complex ⇌ Metabolite

A

Kox = oxidation constant - how readily does oxidation occur? how reactive is the molecule towards CYP450?

114
Q

Why can CYP450s accommodate various substrates?

A

because there are >100 isoforms in man with differently shaped active sites

115
Q

What is the binding of a drug to a CYP450 (and hence Kd) under control of?

A

same as any any other protein-ligand interaction: a combination of enthalpic (bonding) and entropic (predominantly solvent based) effects

116
Q

Which out of the entropic and enthalpic effects are consistent when determining Kd?
Based on this, are lipophilic or hydrophilic drugs more likely to be rapidly cleared?

A

the solvent-based (entropic) factors will always be the same]

  • therefore lipophilic drugs, as their binding is determined mainly by entropic effects
117
Q

What effect describes why the conc of orally taken drugs decreases greatly before reaching the systemic circulation?

A

the first pass effect

118
Q

What equation defines the drug concentration following the first pass effect?

A

F% = Fabs x Fprehep x Fhepatic

Fabs = frac absorbed
Fprehep = least important
Fhep = survived hep clearance
119
Q

Fhep = survived hep clearance

and is mainly determined by?

A

metabolism

120
Q

Fabs = frac absorbed

and is controlled by ?(3)

A

solubiilty/ dissolution/ absorption

121
Q

In the F% equation, what type of drug would we expect to have a lower Fhepatic clearance fraction: lipophilic or hydrophilic?

A

lipophilic, as it would’ve been metabolised a lot already due to its binding to CYP450 being mostly determined by entropic effects

122
Q

What is the most common cause of drug-drug interactions?

A
  • a drug being a CYP inhibitor while patient taking drug metab by CYPs, -> exposure will increase!
    as it’s not as rapidly metabolised
123
Q

How can compounds act as CYP inhibitors?

A

by binding to the metal centre (Fe)

124
Q

what is Kox (eqm of oxidation) determined by?

A

reactivity of molecule towards CYP450

125
Q

What type of heteroatom makes a compound more likely to be a CYP inhibitor?

A
  • unhindered, aromatic nitrogen atoms like in pyridine, imidazole, etc.
  • these have a lone pair which are good at coordinating to iron
126
Q

What does the reactivity of a metabolite correlate strongly with?

A

radical stabilisation

127
Q

What are toxicophores? Why are they not reliable?

A

toxicophores are groups which are commonly metabolised (aka structural alerts) but are not reliable as not all will be bioactivated in certain drugs

128
Q

What are 2 approaches to avoid reactive metabolites?

A
  • exclude chemical functionalities undergoing metabolic activated
  • screen for Reactive Metabolite Formation (RM Assays)
129
Q

What organ is the most common target for small molecule toxicity?

A

the liver - this can be linked to the generation of reactive metabolites

130
Q

Example of reactive metabolite: heteroaromatic compounds

A
  • heteroaromatic compounds can be bio-activated by epoxidation
  • normally removed from system by antioxidant GSH (glutathione) but highly reactive epoxides can also form protein conjugates
131
Q

What are 3 mechanisms of phase II metabolism?

A
  • glucuronidation
  • sulphation
  • glutathione (GSH) conjugation
132
Q

whats toxicity always related to?

A

the dose-

e.g. atorvastatin very effective and admin at very low doses

133
Q

What 4 functional groups normally undergo glucuronidation in phase II metabolism?

A
  • carboxylic acids
  • alcohols
  • phenols
  • amines

when H subbed for the complex ring w OHs and COOH.

134
Q

What 3 functional groups normally undergo sulphation in phase II metabolism?

A
  • alcohols
  • phenols
  • amines
135
Q

What 4 functional groups normally undergo glutathione (GSH) conjugation in phase II metabolism?
(adding GSH)

A
  • halogenated compounds
  • epoxides
  • arene oxides
  • quinone-imines
135
Q

What is idiosyncratic (type-B) toxicity?

A
  • when a phase II metabolite -> toxicity
  • e.g. in some cases, glucuronide can undergo ‘migration’ to form a stable glucuronide (first step)
  • then react with proteins
  • glucuronide levels in some patients can be esp high/ may result in extreme immune response to low levels of alkylated proteins leading to liver injury
136
Q

Example of idiosyncratic toxicity: paracetamol

A
  • paracetamol undergoes phase I metabolism where phenol oxidised to ketone to form active metabolite NAPQI
  • at this point GSH conjugation occurs on aryl ring
  • if GSH levels are depleted, NAPQI accumulates –> non-specific alkylation of proteins in liver
  • > proteins being seen as foreign and activating an inflammatory immune response
137
Q

Genotoxicity: Why do some drugs have the potential to cause genetic mutations (mutagens) or cancer (carcinogens)?

A

they may be able to bind/react with DNA

- this is the mechanism of anti-cancer drugs

138
Q

Mutagenicity models:

Explain how the Ames Test works to assess mutagenicity (in vitro)

A
  • uses bacterial strain Salmonella typhimurium (negative for particular histidine residue)
  • mixed w rat liver extract which requires hisitidine for growth
  • sample added and left to incubate
  • negative result is no mutation as histidine is available an dtherefore no growth
  • positive result is mutation occurring which favours histidine production, causing colonies to grow
139
Q

Mutagenicity models:

What is the accuracy of the Ames test?

A
  • high correlation between animal carcinogenicity and mutagenicity
  • sensitive + predicts ~80% of compounds showing in vivo mutagenic effects
  • however mutagen in test may not necessarily be harmful to humans so further animal and human trials are required
140
Q

Mutagenicity can be attributed to the presence of what functional group?

A
  • a masked aromatic amine
  • can be liberated by in vivo metabolism (e.g. amide hydrolysis)
  • heteroaromatic amines ~20% active in Ames assay
  • anilines ~40% active in Ames assay
141
Q

Case study of celecoxib: what was added to the aromatic ring to alter half life and what was that eventually replaced with and why?

A
  • drug had a short half-life in phase I metabolism
  • introduced Cl in para, preventing introduction of OH during metabolism
    = extended half-life too much however (~1 month) which could cause accumulation + liver toxicity
  • Cl replaced with bioisostere Me = more readily oxidised, giving half life 10-12h ☺
142
Q

Case study of terfenadine:
what was the issue with its metabolism?
What are its 2 types of secondary pharmacology?

A
  • exposure to administered form on left was limited, but active metabolite was main circulating species with carboxylic acid
  • 1st type: when taken with CYP450 drugs, exposure to administered form increased
  • 2nd type: when this initial form had 1000x higher affinity (pIC50 7.6) than active carboxylic metabolite (pIC50 4.8) for K channel in cardiac signalling
  • resulting in channel inhibition causing prolongation of electrical impulses, leading to fatal arrythmias
  • we now instead use the metabolite as the active drug (Fexofenadine) rather than waiting for oxidation to occur
143
Q

what is Cisplatin?

mechanism of action

A

anticancer compound Pt drug
purpose: bind to DNA and kill cancer cells

mechanism of action: potential to cause cancer. desirable in this cance as anti-canc

144
Q

how are amines activated in (Ames assay)?

A

by oxidation -> reactive species that can intercalate and/or alkylate DNA.

145
Q

what does hERG inhibiton lead to? (And what is it)

A

(K channel with key role in cardiac signalling)

= causes prolongation of elec impulses regulating the heartbeat -> fatal arrhythmias

Terfenadine has 1000x higher affinity than the COOH metabolite for hERG = affects signalling :((

146
Q

whats needed for all oxidation steps?

A

CYP450!

147
Q

whats the biggets cause of DDIs?

A

CYP450 inhibition

when taking CYP450 metabolised drugs

148
Q

describe CYP450 inhib toxicity

A

CYP cant oxidise drug, just sat in body

when (propanolol) wears off, OD- systemic as may have took more and seen no effect

149
Q

side effect of oxidation: sec alcohol to ketone?

A

something must be reduced in body:
O2 -> H2O2
liver toxicity

150
Q

when ketone (imine) reduced back to sec alcohol, what must happen in body to keep eqm?

A

something oxidised:

GSH -> GSSG

thiol –S-H –> –S-S–

151
Q

when is GENOTOXICITY most likely to result?

A

(DNA interactions)
bioactivation of aniline: benz-NH2
prone to in body activation

152
Q

when is LIVER TOXICITY most likely to result?

A

from formation of NAPQI
acyl glucoronide- Gluc Phase II

reactive intermediate
fused ring system at bottom- oxidised to form quinone v reac conjugated system

can have inflamm/immune response in liver

153
Q

when iare DDIs most likely to result??

A

aromatic N rings- inhibition of CYP450

fluconazole
right side looks like Haem ring
-> in CYP 450 inhibs
N good at binding to metal (Fe)
-> lots in this molecule!
154
Q

looking at metabolism of drug graph: intensity/ reaction time.

if have 4 peaks (Furosemide example) what do they correspond to?

A

at leats 4 things. may overlap

tallest = parent drug
other 3 = metabolites (structural breaking)

155
Q

etabolism of drug: how to deduce metabolites?

A

tallest = parent drug
other peaks = metabolites (structural breaking)

use MW and see if due to GSH struc etc…

156
Q

3 metabolites of furosemide:

  • N dealkylated product
  • glucoronidation product
  • GSH conjugate..

which is most likely to lead to liver tox and why?

A

C: GSH conjugate

as: A can react w GSH- using up GSH and system vulnerable as GSH consumed C
B: GSH: protein, forming GSH conjugate, removed from body ☺
but if can react w this protein= can react w any protein in body= inflamm, immune response = liver tox

C as GSH=tripeptide, thus likely that molecule can also react w proteins -> immune response

C2 (5 decks)

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