June 1, 2023

Hello everyone my name is jarrett and today i’m going to be talking about the gene drug interaction between sip2b6 and bupropion so what is sip2b6 well sip2b6 is a gene that encodes for the production of the enzyme sip2b6 which is an enzyme of the cytochrome p450 family in general this family of enzymes is the most common family of enzymes in general that we’ll

See in metabolism they metabolize most drugs and they’re found in the liver an estimated one to ten percent of contribution to sip metabolism overall is seen by this enzyme sib 2b6 the enzyme is expressed in higher amounts in females on average about 1.6 fold and that’s in the expression of the enzyme itself when you look at actual mrna expression it’s uh around

Four times folding four times higher expression in females and is in males the most common variant of of sip 2b6 is the sip2b66 haplotype depending on the ethnicity of the patient around 15 to 60 percent of any given population can have this haplotype the main function of sip2b6 in general is to perform a hydroxylation reaction which we’ll see in a minute coming

Up so shown right here is a chart of a common haplotypes and their effects on how the gene is expressed so basically if we look over here what we can see is what we were talking about before the sip 2b6 6 haplotype right here is the most common one uh generally what this will do is it will decrease expression of the enzyme which will decrease activity with

Uh f virus in vivo what f virus is is it’s that hydroxylation reaction it’s the most important and primary reaction that this enzyme carries out these other ones are more minor you can see here the locations that they occur in and yeah most of the genes and most of the most common genes and haplotypes in this gene family um decrease the expression of the enzyme

There are a few as we can see up here like sip two b64 and uh sip two b622 that actually um increase expression of the enzyme they’re not very common though they’ll be seen in a very small proportions of the population so what actually is bupropion well bupropion is an antidepressant it’s an a typical it’s a very atypical antidepressant uh it doesn’t look like a

Lot of things that we’ll see on market today but uh in its own right it’s worked very well as an antidepressant it’s a proof for use in major depressive disorders seasonal affective disorder and smoking sensation it’s got different formulations for all of those and as we talked about before it’s primarily metabolized by sip 2b6 it has other um enzymes that will be

That that will metabolize it which we’ll see on the next slide but sip 2b6 is the major the major enzyme and it’s uh the primary metabolite it’s the primary metabolizing enzyme um sip2b6 is especially important too because it produces an active metabolite uh 6-hydroxybupropion we talked about before on that last slide that reaction that hydroxylates bupropion

And it’s an active metabolite so uh in vitro research has shown or in vivo i’m sorry research has shown that up to 20 times greater auc is seen in the active metabolite as compared to bupropion itself so as you can see that is that is pretty important to the action of this drug um it’s not quite a pro drug but definitely you’re losing a lot maybe even most of

The effectiveness if you decrease the amount of that active metabolite that we’re seeing another thing that’s interesting about bupropion is it has a very unique structure and mechanism as an antidepressant a lot of the antidepressants that we see on market today are uh inhibitors of uh serotonin reuptake but um bupropion inhibits dopamine and norepinephrine

Reuptake as you can see by the structure over here it resembles a lot a lot of our monoamines it looks a little bit like norepinephrine or dopamine it’s a classic phenethylamine as we can see right here so we we’ve talked a little bit about it but what is the actual interaction between bupropion and this enzyme sub 2b6 well as you can see by looking at the

Schematic over here this primary enzyme right here that goes to the primary active metabolite hydroxybuproprion right here that is much stronger than bupropion uh is done through the action of sip2b6 so when we have increased expression of tick of sip two b6 you might have a more effective uh drug because of the fact that you’ll be um just expressing more of it

In general um you’ll be producing more of that active metabolite as compared to things right here such as uh more minor metabolites like this four prime hydroxy bupropion or uh all these other um metabolites down here that are just not active metabolites they’re a lot less effective and not effective at all in the in the slightest um so in thinking about that

We we can think about what inducers and inhibitors of 2b6 might do to a drug so if you have an inhibitor of sip 2b6 it’s going to increase the serum concentration of bupropion and decrease serum concentrations of hydroxybupropion and the opposite for anything that will induce it you can think about that the same way that you would think about the enzyme expression

If we have higher expression of the enzyme we’re going to have less active metabolite and therefore we’re going to decrease the expression of the active metabolite and we’re going to herb the concentration of it rather and we’re going to increase the concentration of bupropion itself now sometimes for some drugs that might sound like a good thing but as we

Talked about before with bupropion the active metabolites very important in the mechanism up to 20 times more potent so for example if we have something like sip2b66 which decreases expression of the enzyme and in turn decreases the use of that epivirus reaction that hydroxylates bupropion we’re going to have a much less effective drug but what what does this

All mean so there are some things that we could do for bupropion um really uh this this interaction in general benefits a lot from the fact that it is part of the cytochrome p450 family of enzymes which are very highly tested for there’s a lot of tests that will test for them they’re very well studied just because they’re so important in metabolism in general

So you have widely available genotyping for uh finding uh different polymorphisms and or at sip2b6 i’m sorry but also 2d6 so it’s it’s pretty it’s pretty easy to get the right idea for a patient on what they might be looking at and what drugs will work and what shouldn’t so i think that really there’s no reason that we shouldn’t be utilizing genotyping more

For this particular interaction now how important is it it’s not really an interaction that’s going to cause many health issues um perhaps if you have an induced enzyme and you have a way too high concentration of the active metabolite you might see a little bit more slightly more toxic effects that are related to dopamine and um norepinephrine such as like

Uh just basic adrenergic and parasympathetic or sympathetic rather effects and things such as psychosis with increased amounts of dopamine so what really in that case knowing all that what do we do if someone actually has a detrimental polymorphism of this gene there aren’t really any guidelines to uh on currently how to proceed with this no one has come out

And said hey if someone has sip2b66 we need to stop using this drug with them it hasn’t been that much of a need for it but um some studies show that the drug might not be effective at all if you are below a certain auc and as such it’s probably a good thing to um to test for uh some of these polymorphisms to make sure that they don’t occur so that we’re not

Wasting our time and not helping the patient because if we’re giving the patient a drug that might not be effective at all and they’re not getting the treatment that they need that’s not good so i think that uh the most useful thing for genotyping in this case would be switching to other options rather than increasing or decreasing doses

Transcribed from video
CYP2B6 and Bupropion By Jarett Drucker