Drug Metabolism 1

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  • Created by: LBCW0502
  • Created on: 03-02-18 13:07
What is the function of Phase I metabolism?
To convert the drug into a metabolite (make the compound more polar and easier to excrete)
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In which tissue does Phase I metabolism predominantly take place?
Liver (hepatocytes, SER)
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What is the function of the hexa-to-penta-coordinated state transition?
The oxidation state of Fe can be changed from Fe 3+ to Fe 2+. Fe has an electron which can be used to bond to an oxygen molecule
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In Phase I, the drug is converted into what?
Metabolites (makes the compound more polar)
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Which type of reactions take place during Phase I?
Oxidation, reduction, hydrolysis, hydration and dehalogenation
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Which reaction occurs the most during Phase I?
Oxidation (adding oxygen into compound)
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What is the main characteristic of a drug?
It is lipophilic (absorbed into tissue)
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What is log P?
Measurement of how lipophilic a compound is (larger value/more lipophilic)
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What is the issue with the properties of a drug?
Lipophilic (unable to be removed). Needs to become more hydrophilic so it is easier to excrete (goes into water component of the body)
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How does changing the nature of a group in a drug affect pharmacological action?
E.g. adding oxygen turns off pharmacological action due to being unable to interact with receptors
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Can metabolites be toxic?
Yes
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In Phase II, the metabolite is converted into what?
A conjugate (added to compound so it is unreactive and gives a 'handle' on compound which is grabbed by transported so it is taken out of cell)
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Which type of reactions take place in Phase II
Sulphonation, glucuronidation, gluthathione, methylation, N-acetylation and amino acid conjugation
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Is it possible to by-pass Phase II?
Yes - metabolite is already water soluble
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Is it possible to by-pass Phase I?
Yes - already a polar compounds (hydrophilic) - e.g. paracetamol has an OH group
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Give an example of Phase I metabolism
Aromatic C-oxidation - compound made water soluble. N-dealkylation (more water soluble). Primary amine added (more soluble). N-oxidation (more polar/charged/water soluble)
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Give an example of Phase II metabolism
Sulphonation or glucuronidation of paracetamol (water soluble/large transporter/charges) - able to be excreted
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How can products be excreted?
Through urine or bile
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Where does biotransformation occur?
In most organs (tissue level). Liver major site (hepatocytes/parenchymal cells). GIT (enterocytes). Lungs and kidneys. Plasma and skin
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Where does biotransformation occur at a cellular level?
SER for Phase I (lipophilic compound partition to lipid). Cytosol for Phase II (adding soluble group to compound and becomes hydrophilic). Small amount in mitochondria (e.g. aspirin metabolised in mitochondria)
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Are there more enzymes involved in Phase I or Phase II?
Phase I
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What are the two most important enzymes in Phase I?
Flavin-monooxygenase and cytochrome P450
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Describe features of cytochrome P450
Contains iron. Isoenzymes. Divides O2, add O to compound
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Describe the nomenclature for CYP
CYP is cytochrome P450. CYP1 (40% morphology). CYP1A (less morphology), CYP1A1 (isoenzyme/most closely related)
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Can CYP enzymes metabolise different types of compounds?
Yes
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Which P450 is used the most in drug metabolism?
CYP3A (relates to drugs/interactions) - followed by CYP2D6, CYP2C, CYP1A2, CYP2E1 (links to ethnicities)
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Describe the structure of CYP isoenzyme
Haem group in active site (able to change oxidation state). Surrounded by four groups attached to nitrogen atoms
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Why are CYP reductase (in the membrane) and CYP close?
Ensures electrons are transferred directly. Don't want electron moving around cell and undergoing oxidation (would damage cell). Stop electron from being lost. Exception - CYP2D6 in cytosol/electrons are thrown (application to ethanol)
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Outline the CYP catalytic cycle (1)
Binding of substrate. Fe held in hex-coordinated state (low spin state)/in plane of ring. Displacement of water. Substrate doesn't interact with iron. Fe is now in penta-coordinated state (pull iron out of plane of ring/energy input). Type I binder
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Type II binder (substrate) contains which atom?
Nitrogen (displaces water/interacts with iron/iron stays in plane)
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Is type II an inhibitor?
Yes
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Outline the CYP catalytic cycle (2)
First electron reduction. Electron from CYP reductase transferred to Fe (becomes 2+). Have electron and energy (able to grab oxygen molecule)
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Outline the CYP catalytic cycle (3)
Oxygen molecule interacts with iron. Pulls iron into plane of ring. Energy/electron form bond between O and Fe (lose double bond in O2)
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Outline the CYP catalytic cycle (4)
Another electron enters. Fe forms a bond with both oxygen atoms. Safely split one of the bonds
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Outline the CYP catalytic cycle (5)
Need to remove one oxygen atom (safest way is to make water - use protons sitting active site). Donate O atom, two protons. Fe (has 7 bonds) is very reactive
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Outline the CYP catalytic cycle (6)
Oxidised substrate. Regeneration of Fe (3+). Give oxygen to substrate. Gap filled by water. Water co-ordinates Fe. Cycle starts again
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What is the purpose of the P450 catalytic cycle?
Convert the drug into a metabolite through a series of enzymatic reactions
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Describe features of FMO
Uses FAD as a prosthetic group instead of Fe. Uses NADPH as a cofactor (able to get electrons) - electrons don't leak
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Outline the FMO catalytic cycle
Enzyme bound to FAD. NADPH binds to reduced FAD to FADH2 (prepared to bind to O2). NADP is oxidised. O binds to FADH2/rearrangement/form bond (hydroperoxyflavin formed). Bind substrate. Break down hydroperoxyflavin. Release NADP/oxidise substrate
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What would happen if the substrate doesn't bind in FMO catalytic cycle?
Becomes unstable. Rearrangement. Formation of hydrogen peroxide (broken down by catalase)
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What are the type of products in P450 and FMO?
ROH for P450 and RO for FMO
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Describe features of P450 and FMO substrate selectivity
Carbons for P450 and primary amines either P450 or FMO (more likely FMO/amines are type II binders/inhibitors of P450 and contains N/stop Fe moving out of plane of ring)
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What is the purpose of the binding of oxygen to FADH2?
Substrate can bind to FADH2-O2 to produce water in an oxidation reaction. If the substrate doesn't bind, then hydrogen peroxide will be produced (toxic)
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Card 2

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In which tissue does Phase I metabolism predominantly take place?

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Liver (hepatocytes, SER)

Card 3

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What is the function of the hexa-to-penta-coordinated state transition?

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Preview of the front of card 3

Card 4

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In Phase I, the drug is converted into what?

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Preview of the front of card 4

Card 5

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Which type of reactions take place during Phase I?

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