Integrated Pharmacology Flashcards
As a refresher, the CYP450 enzymes are heme proteins that are responsile for much of phase 1 drug metabolism in our body. What are the types of phase 1 reactions they catalyze?
Oxidation
Hyroxylation
Dealkylation
Deamination
Hydrolysis
Although there are more than 50 types of CYP450 enzymes, 2 are the most significant for drug metabolism. Which are they?
CYP3A4
CYP2D6
What is the purpose of a phase 1 reaction?
Creation of a reactive functional group on the compound so that the compound can more favorably undergo phase 2 reaction (conjugation). This type of reaction does not typically change the solubility of the molecule very much but alters the biological properties to prime it for phase 2.
True or false: all phase 1 reactions are catalyzed by CYP450 enzymes.
False
True or false: all phase 1 reactions inactivate the drug.
False
True or false: active metabolites of a drug (i.e. the product that results from phase 1 metabolism) may be more potent than the parent compound?
True
What is the purpose of phase 2 reactions?
Increase water solubility by attachment of polar groups by conjugation reactions that also increase molecular mass to facilitate elimination
Where do phase 2 reactions occur?
Cytosol
Are phase 1 or phase 2 reactions faster?
For phase 1 reactions that are catalyzed by CYP450 enzymes, where do these reactions occur?
CYP450 enzymes are embedded in membranes of mitochondria and the ER. Those in mitochondria are primarly responsible for reactions involving substances made by the body, whereas those in the membrane of the ER are involved in reactions with external substances.
What is the most common type of phase 2 reaction?
Glucuronidation - attaches a molecule of UDP to the molecule that underwent phase 1 reaction.
Drugs that undergo glucuronidation are primarily excreted via […]
Feces
What is enteroheptic recycling?
Drugs entering the liver via the portal vein (from intestines) or the hepatic artery (from circulation) may be glucuronidated. The glucuronide metabolite reenters intestine via bile duct and is supposed to be excreted with feces. However, some bacteria of the gut microbiome may be able to produce beta-glucuronidase, which would remove the glucuronide group forming the original drug again. A fraction of this will be reabsorbed and will again reenter the liver via the portal vein to start process again. This increases the half life of the drug.
Describe why grapefruit should be cautioned against when taking most drugs and how it was discovered.
Grapefruit contains a compound that is a furanocoumarin, which inhibits CYP3A4. This makes more of the drug bioavailable than would be in a normal person, so the drug exerts greater effect due to higher bioavailability and longer half life. That explains why they patients experienced the side effects described on the slide. Additionally, the compound in grapefruit juice remains effective in the body for 24 hours, so repeated consumption of grapefruit juice can result in an increase in bioavailability and Cmax due to significant inhibition of CYP3A4.
There are many other drugs that can act as CYP3A4 inhibitors. What is one that is most heavily tested?
Erythromycin
Why is it important to understand pharmacogenetics?
What is pharmacogenetics?
By what mechanism does codeine udergo phase 1 metabolism?
True or false: there is very little genetic variation in the CYP2D6 gene.
False
What is a single nucleotide polymorphism
What are the possible outcomes for a SNP that does cause phenotypic consequences?
What is copy number variance?
