Pharmacokinetics - Metabolism - Phase 2 Flashcards
Cytochorme p450:
- contain a _____ (__) group
- absorb light at ____ nm
- _____ CYPs: ________ distribution of ________
heme (Fe)
450
many - polymorphic distribution of activity
In phase 2 metabolism, all the parts added to drugs are supplied by ______ and are added to the drugs by _________.
co-enzymes
transferases
Glucuronic acid conjugation:
- Drugs carrying a ______ group or a ________ group (less so)
- Enzymes called _______ ______ ________
- co-enzymes called ______
hydroxyl, carboxyl (less so)
glucoronic acid transferases
UDPGA
Describe a drug that would go through glucoronic acid conjugation directly.
Drugs that come into the body with an exposed Hydroxyl (OH) group can undergo this.
Glucoronic acid transferase is a major enzyme in the _____.
liver
What is the purpose of drug metabolism?
To make the drug more polar/hydrophilic meaning that when it reaches the kidney, it will filter out and get excreted from the body
Tylenol can directly go through glucoronic acid conjugation. Why?
Because it enters the body with an already exposed OH group.
Sulfate conjugation (sulfation)
- Drugs carrying a _____ group or a _______ group
- enzymes called _____________
- co-enzyme called ____
hydroxyl, carboxyl
sulfotransferases
PAPS
Sulfotransferases are the major enzymes for phase 2 metabolism in ______. Describe why.
Children.
This is because the liver is not fully developed in kids so, this enzyme is more active than the glucoronic acid transferase.
PAPS is related to what metabolite?
AMP
When tylenol is given to children, what enzyme of phase 2 does it go through?
Sulfotransferases
Glutathione conjugation:
- drugs carrying _____ reactive group that could form a _______ _______
- enzymes called _______ _-_______
- coenzyme called ________
highly reactive group that could form a reactive radical
glutathione s-transferase
Glutathione
glutathione tends to be a ______ agent.
reducing
Conjugation of glutathione occurs where?
at the thiol group
After glutathione conjugation, what occurs?
Drug gets further hydrolyzed to a mercapturic acid conjugate
Acetylation:
- Drugs carrying a ______ _____
- enzymes called ______-__________
- co-enzyme called _____ ____
primary amine
acetyl-transferases
Acetyl-CoA
When the acetyl group is added to a primary amine, what is formed?
Amide
Methylation:
- drugs carrying a ______ ______, ______ or _______
- enzymes called _______-__________
- co-enzyme called _-____________
- primary amine, hydroxyl, thiol
- methyl-transferases
- S-adenosylmethionine
The coenzyme of methylation is also called?
SAM
What is an example drug that can directly go through methylation?
Epinephrine
What is peculiar of methylation?
It actually reduces polarity
What is tylenol?
Acetominophen, an over the counter NSAID
Tylenol:
- toxic dose is _______
- in adults, single doses above ___ grams or ____ mg/kg have a reasonable likelihood of causing _______
- in adults, single dose of more than __ grams or ____ mg/kg have a high risk of _______
variable
- 10, 140, toxicity
- 25, 350, lethality
What is the antidote to acetominophen overdose?
NAC - N-acetylcysteine
Describe NAC
NAC is rapidly metabolized to intracellular glutathione which acts as a powerful antioxidant in the body
When is NAC most effective regarding tylenol overdose?
Most effective when given within 8 hours of ingesting acetominophen - to prevent liver damage
Why is NAC given rather than glutathione?
If a person takes glutathione, acid will cleave off the peptide bond and will not work as an antioxidant
Describe the purpose of drug metabolism.
Phase 1 and 2 drug metabolism tend to increase polarity and water solubility of the drug to increase ease of excretion
What are the different outcomes of drug metabolism?
Deactivation
Trans-activation
Activation
Toxification
Describe deactivation
Metabolites less active then parental molecules, or inactive
Describe trans-activation.
metabolites are as active after biotransformation
Describe Activation
example?
pro-drugs become active metabolites and are responsible for toxicity
ex: morphine
Describe toxification
Example?
Metabolites become toxic
ex: tylenol
