kleinerkiffer
Bluelight Crew
This post is intended to help you understand the connection between the CYP2D6 polymorphism and codeine metabolism.
Codeine is considered a Prodrug, meaning that codeine itself isn't active (it is active to some really small extend but not enough to produce the analgesic effects you want) but the metabolite(s) is/are. The two major active metabolites of codeine are Morphine (via Phase-I metabolism by CYP2D6) and Codeine-6 -glucuronide (via Phase-II metabolism by UGT2B7). Now the research into which one has the major effect isn't clear, as there are papers claiming that C6G is the more important metabolite seen as around 80% of codeine is metabolized into C6G and only around 5-10% is metabolized into morphine (given that you are an extensive metabolizer). But there are good points to the other side as well, so the mystery isn't fully solved afaik.
Now to get into the CYP2D6 polymorphism:
As I said, the CYP450 family (this family includes a bunch of enzymes responsible for Phase-I metabolism) isozyme CYP2D6 is responsible for metabolizing codeine into morphine and given that morphine is way more potent you want as much codeine metabolized into morphine as possible.
You might remember the term allele. If not a quick recap on genetics. You have 46 chromosomes, 23 each from your father and mother respectively. Of those 46 44 chromosomes are called autosomes and the other 2 are called allosome. The two allosomes are responsible for your sex and the remaining 44 are homologue meaning the copy from your father and mother of say chromosome 1 are pretty much identical (they aren't identical to the base-pairs, but they each have the same genes on the same spot) so you have 2 so called alleles for each gene. Now this is important for the polymorphism. Your phenotype is determined by the genotype (the genes you have) and CYP2D6 has a lot of different genotypes.
I'll try to explain it with this graphic:
https://imgur.com/a/a6C6tTB
Here you can see the 4 important genotypes of CYP2D6.
1. Let's start with the poor metabolizer:
In this case you inherited an inactive/faulty allele each from your mother and father. This can happen in a few different ways. The CYP2D6*3 allele for example means that you miss the nucleotide in position 2549, because of this the reading frame shifts and you get a non-functioning enzyme. With this polymorphism your enzyme doesn't work at all (prevalence is around 1-4% in Caucasians). The CYP2D6*4 allele means that at position 1846 the base G was switched to A, this leads to problems with splicing which in turn leads to the loss of enzyme activity (prevalence is around 12-21% in Caucasians). The CYP2D6*5 allele means that the gene just isn't there at all, so no gene no enzyme (prevalence is around 1-7% in Caucasians).
With all these mutations your enzymes aren't working and inducing them will most likely fail to work at all.
2. Intermediate metabolizer:
In this case you either have one functioning and one non-functioning allele (see poor metabolizer for examples) or two mutated genes that have limited function. In this case inducing the enzyme will most likely help to a certain extend.
3. Extensive metabolizer:
This one is the one most people have. Here you have two functioning alleles, also called wild type alleles. This means that your enzymes are working as they should. In this case inducing your enzymes will help.
4. Ultrarapid metabolizer:
In this case you have more than the usual 2 functioning alleles, like 3 or even more. This genotype is called CYP2D6UM allele. In this case you have more functioning enzymes than normally. This can lead to problems as even a therapeutic dose of codeine might be metabolized into more morphine than you can take without risking an overdose. Because of that its advised to try a small dose of codeine first if it's your first time taking codeine, to rule out that you're an ultrarapid metabolizer. Here inducing your enzyme will only lead to more side effects and is really dangerous.
Now what's all the fuzz about inducing enzymes?
Normally your genes are expressed (not sure if that's the right term, in German it's called "exprimieren") at a set rate, let's call it the basal rate. So in a certain amount of time, an hour for example you produce 100 enzymes.
When you induce an enzyme by taking a drug you increase the basal rate. This will lead to more enzymes being produced in a set amount of time, like 200 enzymes instead of the 100 in an hour. Normally this isn't something you want as enzymes metabolize the drugs you take and will decrease the duration of action, so more enzymes = faster metabolism.
But in the case of codeine you want it as you want as much codeine metabolized into morphine as possible.
Drugs that induce CYP2D6 and thus increase the metabolism of codeine into morphine are:
- Glutethimide, this one is a strong inducer, meaning that a lot of CYP2D6 will be expressed leading to an increase of morphine production. But the drug itself is classified as a hypnotic sedative thus increasing the side effects and dangers of codeine. In the worst case this can lead to respiratory depression and death so proceed with caution and start with extremely low doses and have a friend around in case you overdose.
- Dexamethasone, this one has an unspecified potency, meaning that we don't know how strong it induces CYP2D6. The drug is classified as corticosteroid and imo that's a class of drug you shouldn't take if you don't have to as they come with a bunch of serious side effects.
- Rifampin, this one has an unspecified potency as well. Another drug you shouldn't fuck with as it's an antibiotic and popping antibiotics for fun will lead to nasty side effects and bacterial resistance (this is an important problem as we are currently running out of antibiotics, so please don't add to it!).
- Haloperidol, this one has an unspecified potency as well. It's an antipsychotic and imo another drug you shouldn't take if you don't have to as antipsychotics and especially strong ones like haloperidol come with serious and sometimes life threatening side effects (those are rare, but can happen, like torsade de pointes, a kind of arrhythmia that can lead to sudden death; neuroleptic malignant syndrome that can lead to high fever and can lead to your muscles breaking down etc.)
Now to conclude all this, if you really want to induce CYP2D6 the only way imo is with Glutethimide, but even this drug comes with dangers like increased respiratory depression and afaik is really hard to get. So really, there's not much you can do to increase the metabolism of codeine into morphine.
Codeine is considered a Prodrug, meaning that codeine itself isn't active (it is active to some really small extend but not enough to produce the analgesic effects you want) but the metabolite(s) is/are. The two major active metabolites of codeine are Morphine (via Phase-I metabolism by CYP2D6) and Codeine-6 -glucuronide (via Phase-II metabolism by UGT2B7). Now the research into which one has the major effect isn't clear, as there are papers claiming that C6G is the more important metabolite seen as around 80% of codeine is metabolized into C6G and only around 5-10% is metabolized into morphine (given that you are an extensive metabolizer). But there are good points to the other side as well, so the mystery isn't fully solved afaik.
Now to get into the CYP2D6 polymorphism:
As I said, the CYP450 family (this family includes a bunch of enzymes responsible for Phase-I metabolism) isozyme CYP2D6 is responsible for metabolizing codeine into morphine and given that morphine is way more potent you want as much codeine metabolized into morphine as possible.
You might remember the term allele. If not a quick recap on genetics. You have 46 chromosomes, 23 each from your father and mother respectively. Of those 46 44 chromosomes are called autosomes and the other 2 are called allosome. The two allosomes are responsible for your sex and the remaining 44 are homologue meaning the copy from your father and mother of say chromosome 1 are pretty much identical (they aren't identical to the base-pairs, but they each have the same genes on the same spot) so you have 2 so called alleles for each gene. Now this is important for the polymorphism. Your phenotype is determined by the genotype (the genes you have) and CYP2D6 has a lot of different genotypes.
I'll try to explain it with this graphic:
https://imgur.com/a/a6C6tTB
Here you can see the 4 important genotypes of CYP2D6.
1. Let's start with the poor metabolizer:
In this case you inherited an inactive/faulty allele each from your mother and father. This can happen in a few different ways. The CYP2D6*3 allele for example means that you miss the nucleotide in position 2549, because of this the reading frame shifts and you get a non-functioning enzyme. With this polymorphism your enzyme doesn't work at all (prevalence is around 1-4% in Caucasians). The CYP2D6*4 allele means that at position 1846 the base G was switched to A, this leads to problems with splicing which in turn leads to the loss of enzyme activity (prevalence is around 12-21% in Caucasians). The CYP2D6*5 allele means that the gene just isn't there at all, so no gene no enzyme (prevalence is around 1-7% in Caucasians).
With all these mutations your enzymes aren't working and inducing them will most likely fail to work at all.
2. Intermediate metabolizer:
In this case you either have one functioning and one non-functioning allele (see poor metabolizer for examples) or two mutated genes that have limited function. In this case inducing the enzyme will most likely help to a certain extend.
3. Extensive metabolizer:
This one is the one most people have. Here you have two functioning alleles, also called wild type alleles. This means that your enzymes are working as they should. In this case inducing your enzymes will help.
4. Ultrarapid metabolizer:
In this case you have more than the usual 2 functioning alleles, like 3 or even more. This genotype is called CYP2D6UM allele. In this case you have more functioning enzymes than normally. This can lead to problems as even a therapeutic dose of codeine might be metabolized into more morphine than you can take without risking an overdose. Because of that its advised to try a small dose of codeine first if it's your first time taking codeine, to rule out that you're an ultrarapid metabolizer. Here inducing your enzyme will only lead to more side effects and is really dangerous.
Now what's all the fuzz about inducing enzymes?
Normally your genes are expressed (not sure if that's the right term, in German it's called "exprimieren") at a set rate, let's call it the basal rate. So in a certain amount of time, an hour for example you produce 100 enzymes.
When you induce an enzyme by taking a drug you increase the basal rate. This will lead to more enzymes being produced in a set amount of time, like 200 enzymes instead of the 100 in an hour. Normally this isn't something you want as enzymes metabolize the drugs you take and will decrease the duration of action, so more enzymes = faster metabolism.
But in the case of codeine you want it as you want as much codeine metabolized into morphine as possible.
Drugs that induce CYP2D6 and thus increase the metabolism of codeine into morphine are:
- Glutethimide, this one is a strong inducer, meaning that a lot of CYP2D6 will be expressed leading to an increase of morphine production. But the drug itself is classified as a hypnotic sedative thus increasing the side effects and dangers of codeine. In the worst case this can lead to respiratory depression and death so proceed with caution and start with extremely low doses and have a friend around in case you overdose.
- Dexamethasone, this one has an unspecified potency, meaning that we don't know how strong it induces CYP2D6. The drug is classified as corticosteroid and imo that's a class of drug you shouldn't take if you don't have to as they come with a bunch of serious side effects.
- Rifampin, this one has an unspecified potency as well. Another drug you shouldn't fuck with as it's an antibiotic and popping antibiotics for fun will lead to nasty side effects and bacterial resistance (this is an important problem as we are currently running out of antibiotics, so please don't add to it!).
- Haloperidol, this one has an unspecified potency as well. It's an antipsychotic and imo another drug you shouldn't take if you don't have to as antipsychotics and especially strong ones like haloperidol come with serious and sometimes life threatening side effects (those are rare, but can happen, like torsade de pointes, a kind of arrhythmia that can lead to sudden death; neuroleptic malignant syndrome that can lead to high fever and can lead to your muscles breaking down etc.)
Now to conclude all this, if you really want to induce CYP2D6 the only way imo is with Glutethimide, but even this drug comes with dangers like increased respiratory depression and afaik is really hard to get. So really, there's not much you can do to increase the metabolism of codeine into morphine.
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good stuff KK, thanks
