Toxicology🦠 Flashcards
What are 4 key strategies used to look for new drugs?
- follow-on compounds
- computational modelling + sequencing
- serendipitous discovery
- evergreening
What are follow-on compounds?
example?
- 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
What kinds of drugs are produced from serendipitous discovery?
- structurally similar to previously reported drug
- AKA “fast followers” or “me too” drugs
serendipitous discovery drugs have same mechanism as which?
2 examples?
- Same mechanism as the prototype drug but different enough to be considered novel
- e.g. captopril, enalapril
Why are drugs found by serendipitous discovery appreciated by regulators?
- provide professionals & patients with multiple options
- contribute to keeping prices low
What kind of drugs are discovered through evergreening?
- Extreme form of a “me too” drug
- Practically extending the duration of a patent with minimal chemical intervention or changes
computational modelling + sequencing: name of project used and what does the process achieve/entail?
human genome project
increasing num of solved protein x-ray crystal structures
whens computational modelling + sequencing ideal/used?
when step 1: follow on compounds from natural drug doesnt work to get lucky
computational modelling and sequencing requires understanding of what?
the target!
How does esomeprazole relate to omeprazole, and how was it discovered? (3)
- pure enantiomer of omeprazole where alcohol points forwards
- discovered through evergreening
- improved properties: PK profile, resistance to metabolism, conductive to a longer duration
Process to find new drugs
Where do we start when discovering new drugs? (hint: t_ v_, h_ i_)
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
What are the characteristics the of the ‘hits’ identified?
affinity? MW? cLogP? number of rings? HBAs? HBDs?
- moderate affinity (nM - µM)
- low MW (150 < 400)
- cLog P < 4.5
- 1-4 rings
- <8 HBA
- <5 HBD
where to look for new drugs? 3 designs
rational design
high throughput screening
natural products
What type of design is where we look to find hits?
rational design
whats rational design based on and what does it utilise?
- 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
Instead of rational design, what could you use when you don’t know much about your target?
high-throughput screening - screening as many compounds as possible and hope to get lucky
What are 2 types of screens used in high throughput screening?
- unselected screens
- selected (directed) screens
What are the disadvantages of using unselected screens in high-throughput screening?
• 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
What are selected (directed screens) used in high-throughput screening?
- sometimes enough info about target to inform screening
- combo of rational design and unselected screening
What are the advantages of selected (directed) screens?
- faster
- reduces costs
- easier identification of true activity
high throughput screening:
2. selected (directed) screens
num of compounds large -> small
gradual scale
diversity based property based (rational design): target class/ privileged strucs pharmacophore based libraries target specific libraries
What are natural products?
3 examples
- also looked at for when discovering new drugs
- chemicals produced by organisms (commonly fungi, bacteria, plants)
- e.g. salicylic acid, geldanamycin, paclitaxel (Taxol)
Why are natural products difficult to synthesise?
- they are often very complex structures, with multiple stereocentres and macrocycles
- this makes it difficult to control the synthesis
What are PAINs?
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
Why are PAINs problematic?
Time and research money wasted, none could be progressed further
Fragment screening:
What is the rule of 3 (RO3) in regards to lead-like compounds?
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)
What is fragment screening?
A method of reducing ligand complexity to increase the chance of a match with target site
What are the advantages of fragment screening? (3)
- 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)
Describe the process of fragment screening (4)
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
Fragment Screening case study: 7-azaindole
- 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
When is a compound likely to be produced by rational design?
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
When is a compound likely to be produced by a high throughput screen?
flat: few rotatable bonds and high number of sp2 centres
When is a compound likely to be a natural product?
- lots of stereocentres/rotatable bonds
- complex structure
Pan-assay interference compounds are what?
and what are positives from non-specific binding called?
false-positive hit compounds
artefacts
The first stage of turning a hit into a drug is ?
The first stage of turning a hit into a drug is hit-2-lead
What are 4 meaningful prerequisites before starting an optimisation campaign?
- structure must be chemically acceptable
- hit must respond to chemical modulation to generate quantifiable SARs
- need freedom to operate
- favourable ADME profile
What is meant by a hit needing to be chemically acceptable?
the reaction needs to be able to be performed large scale
What is meant by a hit needing to respond to chemical modulation and therefore generating a quantifiable structure activity relationship?
need to be able to change + manipulate (chemically modulate) structure to generate quantifiable structure-activity relationships
What is meant by a hit needing freedom to oeprate?
in terms of intellectual property, the drug needs to be marketable
When does the ADME profile of a hit become clear?
when cross-referenced with toxicology
Once a suitable hit is identified, optimisation occurs across multiple what? Why is the problematic? (3)
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
What percentage of drug candidates entering clinical trials become marketed products?
10%
What ADME process does the low water-solubility of a compound limit?
absorption, as the compound needs to dissolve and be in solution before it can be absorbed
When optimising a compound’s ability to cross the blood brain barrier, what can we modulate?
Example: difference between hydroxyzine and cetirizine
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?
lead optimisation: affect of changing free OH (primary) to COOH?
hydroxyzine -> cetirizine
pka goes from 15 to 5-10.
can no longer cross BBB
Example of imatinib and how changing its structure improved its pharmacokinetics
- amide
- methyl
- extra R group
- adding amide enhanced selectivity
- methyl group increases selectivity by eliminating protein kinase C activity
- extra R group increases sol and oral availability
4 possible strategies used to make changes to a compound to optimise it?
homologation
disjunction
conformational constraining
bioisostere substitution
What is a homologous series?
Series of compounds that differ by a constant unit e.g. CH2
How do we use homologation to optimise a lead?
what does it help us identify?
- 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
describe the second strategy (d…) we use to determine what changes to make to a compound to optimise it?
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
What is the aim of disjunction?
- simplify synthesis
- ‘engineer-out’ activities at unwanted targets and hence rid of side-effects
Example of disjunction: morphine
- 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
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?
conformational constraining:
- freeze drug in a particular conformation (shape in space) to best suit the target)
- uses the lock and key model concept
Conformational constraining is used in molecules with what type of bonds?
rotatable, as these molecules are flexible and can adopt multiple conformations; we need a fixed shape that best interacts with the target
In conformational constraining, what is the ideal conformation called?
how can it be determined?
bioactive conformation
determined: trial and error/ rational
What is one way of identifying the ideal conformation in conformational constraining?
rational design - look at the crystal structures of proteins we’re targeting
2 ways conformational constraining can be acheived?
using substituents and or struc changes
Example of conformational constraining: atenolol, levcromakalim
- 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
What is the fourth strategy (b… s…) we use to determine what changes to make to a compound to optimise it?
bioisostere substitution:
- replace substituents with bioisosteres - have chemical/physical similarities to that it replaces
- results in production of similar biological properties
bioisostere modifications will depend on role of moieties they replaced, what 4 things can be changed/affected?
structural
receptor interaction
PK
metabolism
What properties of a compound will be affected if a bioisostere replaces a STRUCTURAL substituent? (5)
- geometry
- size
- shape
- polarizability
- hydrogen bonding
What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in RECEPTOR INTERACTION?
all parameters
except lipid/water solubility
What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in PHARMACOKINETICS? (3)
- lipophilicity
- pKa
- H bonding
What properties of a compound will be affected if a bioisostere replaces a substituent that has a role in METABOLISM?
metabolic reactivity: reactive metabolites may be important for efficacy
Example of bioisostere substitution: losartan
- carboxylic acid replaced with tetrazole (N type ring)
- same acidic pKa kept as wanted, but lipophilicity increased
how can tetrazoles act as bioisostere for carboxylates?
because have similar pKa :D
Example of bioisostere substitution: soterenol
- 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
as a conformational straining lead modification, what may added to structure to decrease rotation/fitting into diff sites?
bulky constituents (rings)
what 6 systems does drug toxicity affect?
cardiovasc nervous hepatic rep GI renal
What are cardiovascular examples of drug toxicity? 3
- blood pressure changes
- effects on cardiac rhythm
- thrombosis
What are respiratory examples of drug toxicity? (3)
- respiratory suppression
- respiratory constriction
- respiratory inflammation
What are nervous system examples of drug toxicity? (2)
- seizures
- suicide
What is a hepatic example of drug toxicity?
drug-induced liver injury (DILI)
What are gastrointestinal examples of drug toxicity? (2)
- bleeding diarrhoea
- motility effects
What is a renal example of drug toxicity?
drug induced renal injury (DIRI)
What are 5 causes of drug toxicity?
- target driven
- idiosyncratic toxicity
- drug interactions
- carcinogenicity
- generation of reactive metabolites
What is the concept of secondary pharmacology?
- 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
Gibbs free energy diagram of a protein and ligand interacting
unbound P+L
↑
P+L solvated ↓
P+L complex
What does the magnitude of ΔG in the Gibbs free energy diagram of a protein and ligand interaction define?
the strength of the interaction
What unfavourable enthalpic processes lead to us from getting from the solvated protein and ligand up to the unbound protein and ligand?
- loss of ligand-water bonding interactions
- loss of protein-water bonding interactions
What unfavourable entropic processes lead to us from getting from the solvated protein and ligand up to the unbound protein and ligand?
- loss of conformational flexibility in protein
- loss of conformational flexibility in ligand
Is it enthalpically favourable to lose ligand or protein-water bonding?
no, as it results in gaining energy
What favourable enthalpic (energy out) processes lead to going from unbound ligand/protein ↓ to a protein-ligand complex?
- formation of bonding interactions
- energetic changes in protein or ligand
What entropic processes lead to going from unbound ligand/protein ↓ to a protein-ligand complex?
- desolvation of ligands
- return of bound water to bulk state
What enthalpic process that increases energy is important for hydrophilic drugs?
loss of ligand-water bonding interactions, as the hydrophilic drug wanted the water
What enthalpic process that decreases energy is important for hydrophilic drugs?
formation of bonding interactions w protein which is favourable
What enthalpic processes that increase energy are important for lipophilic drugs?
(opposite to hydrophilic!)
- loss of protein-water interactions (didn’t want water in first place)
- energetic changes in protein/ligand
What entropic processes that increase energy are important for lipophilic drugs?
- loss of conformational flexibility in protein
- loss of conformational flexibility in ligand
What enthalpic process that decreases energy is important for lipophilic drugs?
energetic changes in the protein or ligand
What entropic processes that decrease energy are important for lipophilic drugs?
- desolvation of ligands
- return of water to the bulk state
Hydrophilic drugs bind predominantly through what?
bonding interactions
- high requirement for interactions to be optimal for target
- need to pay price of breaking interactions w water
Lipophilic drugs bind predominantly through what?
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
Example of secondary pharmacology: NSAIDs
- 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
why try to make COX2-selective drugs specifically?
COX1 inhib -> ulceration, gastric lining
but
COX2 inhib -> anti-inflamm effects
secondary pharmacology is driven by (2)?
enthalpy and entropic effects
What are the two types of biotransformation (metabolism)?
phase I and phase II
What are the 3 main mechanisms of phase I metabolism?
- oxidation
- reduction
- hydrolysis
What oxidation reactions occur in phase I metabolism? (h… o… d…)
hydroxylation:
- aliphatic
- aromatic
oxidation:
- N-oxidation
- S-oxidation
dealkylation:
- N-dealkylation
- S-dealkylation
- O-dealkylation
example of Phase 1: oxidation: aliphatic hydroxylation?
adding OH to chain coming off benzene ring
example of aromatic hydroxylation?
adding OH onto benzene ring- para position (opposite)
whats N-oxidation?
adding O- onto N = N+
whats S-oxidation (sulfonation)?
R - S -> R - S = O
I I
R R
adding O
Example of N-dealkylation
removing alkyl group from N:
- N - CH3 -> -N - H
Example of S-dealkylation
removing alkyl group from S:
- S - CH3 -> - S - H
Example of O-dealkylation
removing alkyl group/s from O:
- O - CH3 -> - O - H
or
- O - C2H5 -> - O - H
In reduction reactions in phase I metabolism,
what two groups could a nitro group be reduced to?
What is a carbonyl reduced to?
- nitro group → hydroxylamine
- nitro group → amine
- carbonyl → alcohol
In hydrolysis reactions in phase I metabolism, what are esters, amides or phosphates be reduced to?
What is hydrazide reduced to?
- ester/amide/phosphate → corresponding acid and alcohol
- hydrazide → acid and substituted hydrazine
What is the main class of proteins involved in phase I metabolism?
Cytochrome P450s, account for ~60% of commonly prescribed drugs
Where does the main class of proteins catalysing phase I metabolisms carry out oxidations?
in liver cells
How many isoforms of CYP450s are known in man?
> 100, some are synthetic e.g. hormone biosynthesis
What determines the rate of oxidation by cytochrome P450s?
- 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
What is the constant for the equilibrium between the drug and drug-CYP450 complex?
drug ⇌ drug-CYP complex -> Metabolite-CYP complex ⇌ Metabolite
Kd = dissociation constant - binding affinity between protein and drug
Kd drug ⇌ Drug-CYP complex
What is the constant for the equilibrium between the drug-CYP450 complex and metabolite-CYP complex?
drug ⇌ drug-CYP complex -> Metabolite-CYP complex ⇌ Metabolite
Kox = oxidation constant - how readily does oxidation occur? how reactive is the molecule towards CYP450?
Why can CYP450s accommodate various substrates?
because there are >100 isoforms in man with differently shaped active sites
What is the binding of a drug to a CYP450 (and hence Kd) under control of?
same as any any other protein-ligand interaction: a combination of enthalpic (bonding) and entropic (predominantly solvent based) effects
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?
the solvent-based (entropic) factors will always be the same]
- therefore lipophilic drugs, as their binding is determined mainly by entropic effects
What effect describes why the conc of orally taken drugs decreases greatly before reaching the systemic circulation?
the first pass effect
What equation defines the drug concentration following the first pass effect?
F% = Fabs x Fprehep x Fhepatic
Fabs = frac absorbed Fprehep = least important Fhep = survived hep clearance
Fhep = survived hep clearance
and is mainly determined by?
metabolism
Fabs = frac absorbed
and is controlled by ?(3)
solubiilty/ dissolution/ absorption
In the F% equation, what type of drug would we expect to have a lower Fhepatic clearance fraction: lipophilic or hydrophilic?
lipophilic, as it would’ve been metabolised a lot already due to its binding to CYP450 being mostly determined by entropic effects
What is the most common cause of drug-drug interactions?
- a drug being a CYP inhibitor while patient taking drug metab by CYPs, -> exposure will increase!
as it’s not as rapidly metabolised
How can compounds act as CYP inhibitors?
by binding to the metal centre (Fe)
what is Kox (eqm of oxidation) determined by?
reactivity of molecule towards CYP450
What type of heteroatom makes a compound more likely to be a CYP inhibitor?
- unhindered, aromatic nitrogen atoms like in pyridine, imidazole, etc.
- these have a lone pair which are good at coordinating to iron
What does the reactivity of a metabolite correlate strongly with?
radical stabilisation
What are toxicophores? Why are they not reliable?
toxicophores are groups which are commonly metabolised (aka structural alerts) but are not reliable as not all will be bioactivated in certain drugs
What are 2 approaches to avoid reactive metabolites?
- exclude chemical functionalities undergoing metabolic activated
- screen for Reactive Metabolite Formation (RM Assays)
What organ is the most common target for small molecule toxicity?
the liver - this can be linked to the generation of reactive metabolites
Example of reactive metabolite: heteroaromatic compounds
- 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
What are 3 mechanisms of phase II metabolism?
- glucuronidation
- sulphation
- glutathione (GSH) conjugation
whats toxicity always related to?
the dose-
e.g. atorvastatin very effective and admin at very low doses
What 4 functional groups normally undergo glucuronidation in phase II metabolism?
- carboxylic acids
- alcohols
- phenols
- amines
when H subbed for the complex ring w OHs and COOH.
What 3 functional groups normally undergo sulphation in phase II metabolism?
- alcohols
- phenols
- amines
What 4 functional groups normally undergo glutathione (GSH) conjugation in phase II metabolism?
(adding GSH)
- halogenated compounds
- epoxides
- arene oxides
- quinone-imines
What is idiosyncratic (type-B) toxicity?
- 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
Example of idiosyncratic toxicity: paracetamol
- 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
Genotoxicity: Why do some drugs have the potential to cause genetic mutations (mutagens) or cancer (carcinogens)?
they may be able to bind/react with DNA
- this is the mechanism of anti-cancer drugs
Mutagenicity models:
Explain how the Ames Test works to assess mutagenicity (in vitro)
- 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
Mutagenicity models:
What is the accuracy of the Ames test?
- 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
Mutagenicity can be attributed to the presence of what functional group?
- 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
Case study of celecoxib: what was added to the aromatic ring to alter half life and what was that eventually replaced with and why?
- 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 ☺
Case study of terfenadine:
what was the issue with its metabolism?
What are its 2 types of secondary pharmacology?
- 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
what is Cisplatin?
mechanism of action
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
how are amines activated in (Ames assay)?
by oxidation -> reactive species that can intercalate and/or alkylate DNA.
what does hERG inhibiton lead to? (And what is it)
(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 :((
whats needed for all oxidation steps?
CYP450!
whats the biggets cause of DDIs?
CYP450 inhibition
when taking CYP450 metabolised drugs
describe CYP450 inhib toxicity
CYP cant oxidise drug, just sat in body
when (propanolol) wears off, OD- systemic as may have took more and seen no effect
side effect of oxidation: sec alcohol to ketone?
something must be reduced in body:
O2 -> H2O2
liver toxicity
when ketone (imine) reduced back to sec alcohol, what must happen in body to keep eqm?
something oxidised:
GSH -> GSSG
thiol –S-H –> –S-S–
when is GENOTOXICITY most likely to result?
(DNA interactions)
bioactivation of aniline: benz-NH2
prone to in body activation
when is LIVER TOXICITY most likely to result?
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
when iare DDIs most likely to result??
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!
looking at metabolism of drug graph: intensity/ reaction time.
if have 4 peaks (Furosemide example) what do they correspond to?
at leats 4 things. may overlap
tallest = parent drug
other 3 = metabolites (structural breaking)
etabolism of drug: how to deduce metabolites?
tallest = parent drug
other peaks = metabolites (structural breaking)
use MW and see if due to GSH struc etc…
3 metabolites of furosemide:
- N dealkylated product
- glucoronidation product
- GSH conjugate..
which is most likely to lead to liver tox and why?
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
