Lesson 5 Flashcards
Which kind of species-related differences are present in phase II enzymes?
These differences can be both qualitative (the enzyme may be absent or result in a non-functional protein) and quantitative (ezymes are expressed at a different extent)
Which are the phase II differences in pigs?
In pigs there’s a large prevalence of glucoronidation over sulphation. This is particularly true for aromatic substrates
OPEN QUESTION: Which are the differences in phase II in felines?
- glucoronidation: non-functional because of structural defect in UGT1A6 and UGT1A9, expecially for aromatic molecules. It results in problems in the administration of most drugs (aromatic)
- N-acetylation: not particularly efficientt because of the lack of NAT1, there’s only NAT2
- glycination: decreased, we don’t know the reason
Which are the differences in phase II in dogs?
They lack of NAT1 and NAT2 genes and have some side pathways in order to cope with this lack of N-acetylation. For this reason, sulphonamides should not be overdosed
Which are the factors that influence DME expression?
Specie, breed, age, gender, disease
Which is the difference between beagle and greyhound in biotrasformation?
greyhound are not able to hydroxylate propofol (anesthetic), their Vmax is 3 times less than beagle. For this reason, you must adjust the dose of anesthetic according to the breed
Which is the difference between beagle and greyhound in biotrasformation?
greyhound are not able to hydroxylate propofol (anesthetic), their Vmax is 3 times less than beagle. For this reason, you must adjust the dose of anesthetic according to the breed
How can we measure the oxidative P450-mediated metabolism?
We can use antipyrine, a drug which is completely metabolized by cytochrome P450. It’s disappearance is directly connected to the biotransformation capacity
Which difference can be found between young and old animals?
The main difference is the oxidative P450-mediated biotransformation ability.
Furthermore, in young animals there are no gender-related differences while in older animals there are great differences between gender.
Are there any differences between gender in human (about biotransformation)?
CYP1Ain more expressed in male while CYP2D is more expressed in women.
Which are the consequences of a disease on biotransformations?
- cytokines lead to a decrease transcritpion of all the P450s decreasing the drug metabolizing enzyme efficacy
- acute-phase proteins present in plasma are able to carry xenobiotics altering the kinetics of drugs
Definition of induction
Increase in the overall biotransformation capacity of an organism due to the increased number of enzymatic molecules. It is caused by the prologed exposure to a given substrate and particularly to inducers
Which drug metabolising enzymes are inducible?
Enzyme induction does not involve all xenobiotic metabolising enzymes and it may occur mostly involving phase I enzymes such as CYP1A, reductases (which are not so inducible), microsomal esterases, amidases. In phase II only UGTs and GTSs.
All the other Phase II enzymes are not inducible.
OPEN QUESTION: Which are the consequences of the continuous administration of phenobarbital?
It is a large planar molecule which will cause a large number of enzymes to be induced: CYP2B, CYP3A, CYP2C, NADPH cytochrome p450 reductase, selected isoforms of microsomal esterases and amidases, certain isoforms of UGT and GST. So the side effect is a permanent state of induction which influence the therapeutic effect of every other drug administered to the patient.
We have also a lot of endogenous substrates which are biotransformed by metabolising enzymes: thyroid hormones, sexual steroids, corticosteroids. In case of induction by phenobarbital, you should always monitor some physiological and sexual functions, in terms of all the periodic cycles in women etc.
For this reason, this drug should be administered in cycles.
Which mechanisms allow DME induction? (list)
- increase of mRNAs transcription
- protein stabilization
- AhR reactive compounds
