L6: Drug metabolism part 2 Flashcards
P450 catalytic cycle?
chatgpt. maybe research more
Cytochrome P450 Catalytic Cycle (Simplified)
Substrate Binding
The substrate (RH) enters the active site of cytochrome P450.
This causes a conformational change, making the iron in the heme more reactive.
First Electron Transfer
An electron is transferred from P450 reductase (via NADPH) to the heme iron, reducing Fe³⁺ (ferric) → Fe²⁺ (ferrous).
This reduced Fe²⁺ state is necessary to bind oxygen.
Oxygen Binding
Molecular oxygen (O₂) binds to Fe²⁺ in the heme group, forming an Fe²⁺–O₂ complex.
Second Electron Transfer & Oxygen Activation
A second electron is donated (again from NADPH via P450 reductase), reducing O₂ to O₂²⁻ (peroxide-like state).
The iron transitions back to Fe³⁺, helping stabilize the oxygen activation.
Oxygen-Oxygen Bond Cleavage
One of the oxygen atoms is reduced and released as water (H₂O) using protons (H⁺) in the active site.
The remaining oxygen atom is now a highly reactive iron-oxo species (Fe⁴⁺=O, known as Compound I).
Substrate Oxidation (Hydroxylation)
This reactive Fe⁴⁺=O species inserts oxygen into the substrate (RH → ROH).
This is how drug molecules are oxidized in metabolism.
Product Release & Enzyme Reset
The hydroxylated product (ROH) is released, and the enzyme returns to its resting Fe³⁺ state, ready for another cycle.
C-oxidation?
arbon Oxidation (C-Oxidation)
Happens on alkyl chains (straight or branched).
Affects molecules with benzylic, allylic, or aliphatic carbons.
Example: Warfarin undergoes C-hydroxylation at specific positions.
If an O-ethyl or O-methyl group is present, the carbon attached to the oxygen can be oxidized, leading to O-dealkylation (the oxygen remains, but the alkyl group is removed as an aldehyde or ketone).
- C-Oxidation Leading to Dealkylation
If an alkyl group (e.g., methyl, ethyl) is attached to a heteroatom (O, N, S), oxidation at the adjacent carbon can result in dealkylation (removal of the alkyl group).
Common with O-, N-, and S-dealkylation reactions.
Example: If you have N-methyl, oxidation leads to N-demethylation (methyl group is removed).
- Sulfur Oxidation (S-Oxidation)
Sulfur-containing drugs can be oxidized to form sulfoxides (S=O) or sulfones (O=S=O).
Example: Imipramine undergoes S-oxidation.
Important for metabolism of thiols, thioethers, and sulfonamides.
- Nitrogen Oxidation (N-Oxidation)
Primary, secondary, and tertiary amines undergo oxidation at nitrogen.
Tertiary amines → N-oxide formation (e.g., imipramine forming an N-oxide).
Primary aromatic amines → converted to hydroxylamines or even further to nitroso compounds, which can be toxic.
- Primary Aromatic Amines Oxidation
Can occur on aromatic rings or straight-chain amines.
Example: Aniline (C₆H₅NH₂) can be oxidized to a hydroxylamine (C₆H₅NHOH) and further to nitroso (C₆H₅NO).
General Takeaways
C-oxidation happens mostly on straight alkyl chains or benzylic positions.
If O-ethyl or O-methyl groups are present, oxidation removes the alkyl group (O-dealkylation).
N-oxidation affects tertiary amines (N-oxides) and primary amines (hydroxylamines → nitroso).
S-oxidation affects sulfur-containing drugs, forming sulfoxides or sulfones.
there are pictures and examples and deffo verify this is right cus this is chatgpt
non p450 drug metabolism?
Oxidations
– Flavin mono-oxygenase
– Alcohol dehydrogenase
* Hydrolyses (anything which is hydrated or hydrating idk what he said)
– Epoxide hydrolase
* Conjugation (Phase 2)
– Glucuronidation (high capacity)
– Sulphation (low capacity)
– Acetylation (variable capacity)
conjugations?
conjugations: glucuronidation (UGTs) and sulphation (SULTs)
. Does Conjugation Need to Go Through Phase I First?
Not always! Some drugs/metabolites can directly undergo Phase II metabolism without needing Phase I oxidation or hydrolysis.
Example: Paracetamol can be directly glucuronidated or sulfated without Phase I.
But in some cases, Phase I makes the drug more reactive, preparing it for Phase II (e.g., hydroxylation making the molecule more prone to conjugation).
- Glucuronidation (Corrected Explanation)
Enzyme: UDP-glucuronosyltransferases (UGTs, not “gluconisol transferases”).
What happens?
Adds UDP-glucuronic acid to hydroxyl (-OH), carboxyl (-COOH), or amine (-NH₂) groups.
Increases water solubility, making it easier to excrete in urine or bile.
Common for: Drugs with -OH groups (e.g., morphine, paracetamol).
- Sulfation (Corrected Explanation)
Enzyme: Sulfotransferases (SULTs, not “sulphide transferases”).
What happens?
Adds a sulfate group (-SO₄²⁻) to hydroxyl (-OH) groups.
Highly polar and charged, making the drug very water-soluble and easily excreted in urine.
Comparison with glucuronidation:
Sulfation is smaller but more charged, whereas glucuronidation adds a larger bulky group.
Glucuronidation dominates when high doses of a drug are taken (sulfation becomes saturated more easily).
- Conjugation and Toxicity
Phase II metabolism usually detoxifies drugs.
But some Phase I metabolites are highly reactive, so Phase II conjugation makes them safer for elimination.
Example:
Paracetamol’s normal metabolism involves glucuronidation and sulfation.
But in overdose, a toxic NAPQI metabolite forms (via Phase I oxidation by CYP enzymes).
If glutathione conjugation (a Phase II reaction) fails, NAPQI builds up and causes liver damage.
factors that affect drug metabolism?
instrinsic: genetic: polymorphism of drug-metabolising enzymes, adme
age, body weight, diseases/conditions, kidney function, liver function
extrinsic: alcohol, diet, diseases/ conditions (as some are acquired), smoking
drug-drug interactions- CYP3A4?
- Responsible for largest number of drug
biotransformations - Major site of expression is liver
– Some in small intestine - 20-fold variation in metabolic activity
amongst individuals - Wide substrate profile
Inhibitors will increase conc of drug, inducers will increase metabolism by making more enzymes?
CYP3A4
* Notable substrates:
– Cortisol, ciclosporin, erythromycin,
testosterone, midazolam, terfenadine
* Notable inhibitors
– Grapefruit juice, gestodene, ketoconazole
* Inducers
– Barbiturates, rifampicin, dexamethasone
terfenadine?
- Non-sedative, antihistamine (H1) drug
- A pro-drug
– Prodrug has antiarrhythmic properties - Major routes of metabolism:
– Oxidative N-dealkylation
– Stepwise oxidation of tert-methyl group to
primary alcohol followed by carboxylic acid to
produce pharmacologically-active compound
Prodrug tends to be more easily absorbed
look at pic of terfenadine metabolism and toxicity
terfernadine- a case history and its effect on cardiac function?
Case history: 29-yr old male
* Terfenadine 2xday for hayfever
* Consumed 2xglasses grapefruit juice with
dose & then mowed his lawn
* Collapsed and died from heart attack
– terfenadine is a prodrug
* accumulation causes Torsades des Pointes (Long QT
syndrome)
– bergamottins inhibit CYP3A4
* responsible for conversion of prodrug into active form
Genetic polymorphisms
* Upto 95% of patient variability in individual
response is due to genetic factors
* Affects both Phase 1 and Phase 2
enzymes
– Polymorphisms in Phase 1 enzymes more
clinically relevant
Phase 1 more important- detoxifying getting rid og drug
Muateted so u cant do that= conc goes high and that can cause toxicity
SNPs?
- SNPs are individual
changes in DNA sequence
from the consensus - Give rise to allelic
variations - Define individuality
– Many are benign, some
are not - Often persist over several
generations because of a
lack of selective advantage
– E.g. blood group, hair
colour
Single base change in a molecule that affects the codon, amino acid, protein
Importance depends on amino acid
Aspartate for glutamate- basically same
Valine for glutamate?
metabolic phenoypes and polymorphisms?
look at the images omg
Knowing how its metabolised, what route its metabolised by and how it varies in population helps when designing drugs.
thnic variation
* CYP2C8
– *2 predominates in Africans
– *3 predominates in Caucasians
* CYP2C9
– Predominantly Caucasians
– 3>2 in effect upon metabolism
* CYP2C19
– *2 & *3 Africans>Asians=Caucasians
Polymorphisms in Phase 2 - UGTs
* Most common in promoters
* Crigler-Najjar-1 syndrome
– fatal
* CN-2 syndrome
– survivable
* Gilbert’s syndrome
– relatively mild
– inability to glucuronidate bilirubin
– most common polymorphism
– 19% of some ethnic groups
Cant glucorinate idk spelling things
Have sulphation and ?? conjugation can take up the slack
Polymorphisms in ugts- jaundice?
