L6: Drug metabolism Flashcards
what makes an ideal drug?
What makes an “ideal” drug?
* Readily absorbed after oral administration
* Not metabolised (dont want to get rid of effect and if not metabolised then can give lower dose so safer and doesnt produce more toxic metabolites)
* Pharmacodynamic target readily accessible
and only site of high-affinity binding
* High therapeutic efficacy
* Extensive therapeutic window
* Optimal plasma half-life
– Long enough to have desired effect
– Short enough to avoid accumulation and toxicit
why might a NCE be subject to drug metabolism?
NCE- new chemical entity
* Cells have evolved enzymes to metabolise
endogenous compounds
– Synthesis of cellular components
– Biochemistry of the cell – “life processes”
* Cells have also evolved enzymes to
metabolise exogenous compounds
– Present in diet, environment, etc.
* detoxification
– Compounds are no different in aspect compared
with endogenous compounds
Why might and NCE be subject to
drug metabolism?
* Drugs are no different to endogenous and
exogenous compounds
* Use the same metabolic enzymes involved
in endogenous and exogenous
metabolism
– “Highjacking” of endogenous biochemical
machinery
– This is why drug-drug and drug-dietary
interactions occur
What is drug metabolism?
drug—>metabolite—-> conjugate
Drug metabolism converts drug to metabolite and then a conjugate. Making molecule more polar by taking off oxygen atom?
Conjugate- attaching transporters???
So it can be excreted.
where does drug metabolism occur?
- extrahepatic microsomal enzymes: conjugation, oxidation
hepatic microsomal enzymes- oxidation, conjugation
hepatic non microsomal enzymes- acetylation, sulfation, GSH, alcohol/aldehyde, dehydrogenase, hydrolysis, ox/red
main site is your liver
Phase 1 Metabolism (Modification – oxidation, reduction, hydrolysis)
Primarily occurs in the Smooth Endoplasmic Reticulum (SER)
Cytochrome P450 enzymes (CYPs), which are crucial for oxidation reactions, are located in the membranes of the SER
Some hydrolysis reactions can also occur in the cytosol or plasma
Phase 2 Metabolism (Conjugation – adding a polar group for excretion)
Mostly occurs in the cytosol, except for glucuronidation, which happens in the SER
Conjugation reactions (e.g., glucuronidation, sulfation, acetylation, methylation, and amino acid conjugation) occur here
Mitochondria (Rare Metabolism)
Amino acid conjugation (e.g., glycine or glutamine conjugation of some drugs) can occur in the mitochondria
Some monoamine oxidase (MAO) metabolism of neurotransmitters occurs in the mitochondria
phase 1 vs phase 2?
phase 1: drug———> metabolite (oxidation, reduction, hydrolysis, hydration, dehalogenation
95% through ox
phase 2: metabolite——–> conjugate (sulphation, glucuronidation, glutathione, methylation, N-acetylation, amino acid conjugation
phase 1
Phase I metabolism consists of reduction, oxidation, or hydrolysis reactions. These reactions serve to convert lipophilic drugs into more polar molecules by adding or exposing a polar functional group such as -NH2 or -OH. These reactions also often create active metabolites and which is beneficial in activating prodrugs into their active and therapeutic state. Phase I includes the use of the cytochrome P450 system found with the membrane of the endoplasmic reticulum. If the CYP450 system becomes inhibited in any way the drug level will increase, and vice versa if induced, the drug level will decrease.
Phase I reaction using the CYP450 system includes both an oxidative and reductive step using NADPH and not ATP: Drug + O2+ NADPH -> Drug*+ H20 + NADP+.
- https://www.ncbi.nlm.nih.gov/books/NBK544353/#:~:text=Phase%20I%20metabolism%20consists%20of,as%20%2DNH2%20or%20%2DOH.
Biotransformation of the compound to
make it more polar
– Oxidation, reduction, hydrolysis
* Changes in biological activity
* Results in the activation of the compound
for the addition of Phase II conjugate
– Activation also makes the compound more
reactive, thus more potentially toxic
chat: Introducing lone pair-containing groups (e.g., hydroxyl, amine, or carboxyl groups) enables hydrogen bonding, which increases the molecule’s reactivity and polarity, making it more amenable to further conjugation reactions. This is particularly relevant in drug metabolism, where such modifications help prepare the drug for phase II metabolism, enhancing water solubility for excretion.
In the context of prodrugs, these modifications can also be used strategically to activate the drug. A prodrug is typically administered in an inactive or less active form, and then metabolized into its active form within the body.
Meanwhile, metabolites—especially those formed in phase I metabolism—can become more chemically reactive than the parent compound. This increased reactivity can lead to toxic effects, as these metabolites may bind covalently to proteins, nucleic acids, or sugars, potentially disrupting cellular function and triggering adverse reactions.
phase 2?
Conjugation reaction, usually to make the
compound larger and more water-soluble
* Addition of a large, water-soluble
compound
– Almost always results in detoxification
– Increases chances of excretion
– Many cellular transporters are targeted to
Conjugates
So can be grabbed by transporters and transporters out.
Went from complicated molecule to something quite simple.
Conjugate helps it be secreted.
the challenge to the sequential phase concept?
Phase 2 does NOT always need Phase 1
* Phase 2 does NOT always occur
Phase 1 makes molecule more soluble so it may be excreted straight away
*need to learn structure of paracetamol not to remember it but to recognise it
Tefenedine? Too
oxidations, reductions, conjugations, nucleophillic trapping processes
Oxidations
– Cytochrome P450, flavin mono-oxygenase, alcohol
dehydrogenase etc.
* Reductions
– Small group of processes, mainly nitro- and azo-
Reductions. Introducing electrons for hydrogen bonding?
* Conjugations
– Addition of electrophilic adenosine-containing
cofactors (PAPS, acetyl coenzyme A, UDP-glucuronic
acid, S-adenosylmethionine). Adding a cofactor to the moleu cle
* Nucleophilic trapping processes
– Mainly reactions of GSH with electrophilic
xenobiotics, also DNA and protein adduct formation
drug metabolism enzymes?
Cytochrome P450 isoforms
Superfamily of haem-thiolate proteins (40 –
65 kDa) that exist in multiple isoforms
* Responsible for the majority (>90%) of all
xenobiotic oxidation reactions
* Expressed in a variety of tissues
– Liver»>GIT>Kidney>lungs=skin
* Present in the smooth endoplasmic reticulum
in close association with cytochrome P450
reductase
– Provides electrons for catalytic cycle
Nomenclature
CYP Cytochrome P450
* CYP1 Family name, > 40% aa
identity with any other CYP
* CYP1A Sub-family, > 55% aa identity
within family with other CYPs
* CYP1A1 Isoenzyme
CYP 1A1
1= grand-parent
A= parent
1= sibling
classification of human p450s based on major substrate class:
xenobiotics- 1A1 (cigarette smoke?), 1A2, 2C8, 2E1 (metabolises acohol) etc. maybe look at the table.
haem-thiolate group?
maybe look at the image
Iron (Fe) in the heme group is essential for the enzyme’s function.
The primary role of cytochrome P450 enzymes is to break oxygen-oxygen bonds in molecular oxygen (O₂) and insert one oxygen atom into the substrate (oxidation reaction).
P450 reductase is an enzyme that helps transfer electrons from NADPH to the heme iron in cytochrome P450.
The iron in the heme group can switch between Fe²⁺ (ferrous) and Fe³⁺ (ferric) states, allowing it to accept and donate electrons, which is critical for oxygen activation.
The heme iron is coordinated to nitrogen atoms within the porphyrin ring, which stabilizes it.
A cysteine thiol (-SH) group in the active site acts as an axial ligand, anchoring the iron in place and enhancing its reactivity.
