Chapter 4: Biotransformation Flashcards
Test 1
Describe drug biotransformation and the difference between a prodrug and an active drug.
Biotransformation is where the drug is metabolized and can become more or less active. Typically makes the drug more water soluble and easier to excrete
A prodrug is an inactive form of a drug that gets activated by being metabolized in the body.
An active drug is already active as is and can interact with its target
Describe the first pass effect, and the route of blood through the liver.
The first pass effect is where a medication is taken PO and its metabolized by the liver before reaching the CVS
The route of blood through the liver is that the blood comes from the GI tract intestinal veins — Portal vein – Hepatic sinuses (leaky capillaries on sinuses and hepatocytes where drug is metabolized and/or excreted) — hepatic vein — vena cava — heart
* not first pass effect* IV drug route
Hepatic artery — hepatic sinuses — hepatic vein — vena cava — heart
Where does biotransformation most occur?
The liver
List the major phase I and phase II metabolic reactions. Know which P450 isoforms are responsible for the greatest number of important reactions.
Major Phase 1 metabolic reactions: Oxidation, reduction, hydrolysis
Major Phase 2 metabolic reactions: Conjugation reactions (attaching something on, essentially making it bigger and more hydrophilic)
P450 isoforms: CYP3A4 is the most important because it is responsible for the greatest number of metabolism reactions
Where does the blood come from in the hepatic sinuses?
The Hepatic artery and the hepatic portal vein
Both oxygenated and deoxygenated blood
What are the hepatocytes?
The functional units in the liver in the hepatic sinuses where drugs are metabolized
What are phase 1 reations in the liver?
Converts drug to more polar metabolite (most drug inactivated)
Adds or unmasks functional groups (-OH, -NH, -SH)
Consist of oxidation, reduction, hydrolysis
Lipophillic becomes hydrophilic (more easily excreted)
Is Phase 1 always followed by phase 2?
No.
What does oxidation mean?
Loss of electron
What does reduction mean?
Gain electron
What type of reaction is Cytochrome P450?
Oxidation
What happens in the Cytochrome P450 oxidation reaction?
Cytochrome P450 enzyme converts a drug into a more polar metabolite.
The drug binds to P450[Fe+++]
You go through a series of oxidation and reduction reactions
NADPH is a reducing compound and becomes oxidized (NADP+)
Which reduces and oxidizes the Flavoprotein.
The Flavoprotein reduces the P450
O2 and 2H bind to the compound
Water is released (hydrolysis)
-O is attached to the drug now; which makes the drug more hydrophilic
The P450 enzyme is now removed and now the new metabolite exits the cycle.
What does CYP mean?
Cytochrome P450
CYP3A4/5 are resposible for _____ of drugs going through phase 1 reactions?
50%
Define what is meant by “wild type” CYP enzymes, and how they are notated.
*1
Most common polymorphic variant
Most common uncommon
Where does the Cytochrome P450 metabolize?
In the ER of the hepatocytoes
There are over _____ human P450s
50
How do you identify a CYP polymorphic variant?
*#
Ex) *5, *2
*1 is ALWAYS the wild type
Describe the mechanism of hepatic enzyme induction and inhibition.
Hepatic enzyme induction occurs when a drug increases the expression and activity of metabolic enzymes, leading to faster metabolism of other drugs. Enzyme inhibition occurs when a drug decreases the activity of metabolic enzymes, leading to slower metabolism of other drugs.
What happens when Drug1 is being inactivated by CYP3A4… and you start taking another drug that is an inducer of CYP3A4?
Drug 1 will become inactivated at a faster rate
What happens when Drug 1 is a Prodrug that is activated by CYP3A4… and you start taking a drug that is an inducer of CYP3A4?
The Prodrug will be activated faster
Might reach toxic levels more quickly
What happens when Drug1 is being inactivated by CYP3A4… and you start taking another drug that is an inhibitor of CYP3A4?
Drug 1 becomes more active
What happens when Drug 1 is a Prodrug that is activated by CYP3A4… and you start taking a drug that is an inhibitor of CYP3A4?
The prodrug will not be activated as fast
Describe the pathways by which acetaminophen is metabolized (1) to harmless products if normal doses are taken and (2) to hepatotoxic products if an overdose is taken.
Acetaminophen is normally metabolized by phase 2 conjugation reactions glucuronidation and sulfation to form non toxic byproducts that are excreted through feces and urine.
If you overdose on acetaminophen, Phase 1 metabolism reactions are activated with CYP2E1 and CYP3A4. This builds up reactive toxic intermediates with positive charges that can attach proteins and other negatively charged molecules.
If its not that bad, a glutathione will attach to the charge (another phase 2 conjugation reaction) and the byproduct is swept away.
If it is really bad like a whole bottle, then we eventually run out of glutathione and Nucleophillic Cell Macromolecules (protein-SH) will attach to charge and inactive them and lead to liver cell death.
CYP2B6
Percentage
Substrates
Inducers
Inhibitors
8%
Bupropion, Ketamine, methadone, propofol
Phenobarbital, cyclophosphamide
Ticlopidine, clopidogrel
CYP2D6
Percentage
Substrates
Inducers
Inhibitors
20%
Haloperidol, oxycodone, metoprolol, tricyclic antidepressants
Unknown
Quinidine, paroxetine
CYP3A4
Percentage
Substrates
Inducers
Inhibitors
50%
Acetaminophen, amiodarone, lidocaine, midazolam… extensive list relevant to anesthesia drugs….
Barbiturates, phenytoin, carbamazepine, glucocorticoids
Diltiazem, grapefuit juice, erythromycin, fluconazole
What does Brussel sprouts do?
Inducer of CYP1A2
What is warfarin activated by?
CYP1A2
What is codeine?
A prodrug
Its activated by CYP2D6 into Morphine or another active codeine metabolite
What is Glucuronidation?
Phase 2 metabolism in the liver that adds glucuronic acid
more hydrophilic = more excretion
What is GST enzyme?
Adds Glutathion-S-transferase
Everywhere ESPECIALLY in RBC because high amounts of oxidants
Important in detoxification
more hydrophilic = more excretion
What happens when you overdose?
You overwhelm the normal pathways for metabolizing a drug and alternative pathways are activated creating toxic byproducts.
What is treatement for tylenol overdose?
N-Acetylcylsteine (NAC)
Activated charcol
