Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:32 Welcome to HelixTalk episode 167 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is beyond one size fits all, unraveling the genetic tapestry of CYP2D6 drug metabolism. So Dr. Patel, today we're talking about variations, genetic variations, of this enzyme in your liver called CYP2D6. We're going to focus on how that has implications with drug metabolism. Dr. Khyati Patel 00:58 And this is really exciting. Dr. Kane, you know, you and I, at some point have taught in our Clinical Pharmacogenomics course, and I heavily deal with the warfarin world. So you know those CYP enzymes, and we have done a previous recording on warfarin polymorphism and how it has impact on warfarin therapy. I'm excited to learn about CYP2D6, and how those variations can impact drug therapy. Dr. Sean Kane 01:27 You know, Dr. Patel, instead of a patient case, I want to kind of have a thought experiment here, and this is really something that anyone could think of, whether they're a healthcare provider or not. But did you ever wonder, why is it that certain drugs work better in some patients versus others. Or why is it that sometimes patients are really sensitive to a drug where even a small dose really gives them a lot of side effects, whereas another patient, they do very well with that, they don't have a problem with that. Dr. Khyati Patel 01:53 Yeah, and personal experience, you know, got a wisdom tooth pulled and was given an Orco and it did not cut the pain at all, but it caused multiple projectile vomiting, so I definitely was on the side effect spectrum rather than therapeutic relief spectrum with that one. And so yeah, this kind of rides along with Dr. Sean Kane 02:14 that, yeah. And it really shouldn't be surprising to the listener that in many of these cases, and not all, but many of these cases, genetic differences or pharmacogenomic differences, do account for the reason why a drug behaves differently in different humans, and that's actually the focus of today's episode is we're going to talk about how genetic differences in one specific hepatic enzyme called CYP2D6 can cause some pain medications to not work at all in some patients and then in other patients, is really potent to the point where they get toxicities, projectile vomiting, like you mentioned, that can tell respiratory depression. Also antidepressants use this pathway. So some antidepressants in certain patients will have basically no effectiveness at all, whereas in other patients, you'll see lots of side effects because it works too well, the drug levels are too high for those patients. And of course, we'll go through not just that. There are kind of rules of thumb with different drugs that use this pathway, but the why behind it, and I think that's the most important part for the pharmacist to understand, is the mechanism behind why certain patients are going to respond differently based on their genetics to these medications. Dr. Khyati Patel 03:21 Like you said, Dr. Kane about the pain medication or antidepressants with 26 the response is different, and I think our podcast kind of revolves around that, but it's mind boggling to see that 2d six can metabolize up to 20 to 25% of drugs that are out in the market. And so obviously, you know, our time here today is very limited, and we're going to focus on these true but it's it's amazing how there are multiple different drugs that could be impacted by this particular enzyme. Dr. Sean Kane 03:53 What's even crazier, Dr. Patel, is that there's at least 150 variants of this enzyme. So that means that we've identified at least 150 different ways that humans can have this two to six enzyme. And some humans, when they have a variant of this can be normal. Call those kind of wild type or normal function metabolizers. But some patients can have way too much of this enzymatic activity. We call them Ultra metabolizers, whereas other people can be on the opposite end of the spectrum, and they can basically have little or no two to six activity. We call those poor metabolizers. Dr. Khyati Patel 04:32 And essentially it's a metabolizing enzyme so it it will convert the drug into more active metabolite, which would have therapeutic effect. But, you know, depending on the patient, it could also have toxic effect. But in certain cases, it could also work on pro drugs. So pro drugs are not active, but it needs the enzyme, the 2d six, in order to convert it to an active drug altogether. Dr. Sean Kane 04:59 So then logic. Dr. Patel, it depends on kind of what the role of CYP2D6 is in terms of the disposition of a drug. So for example, if someone has a lot of 2d six activation and a drug needs that to be active, then they're going to kind of hyper convert that to an active compound and maybe cause too much of a drug effect. Or if a patient has too much of this two to six activity, and that is the enzyme responsible for getting rid of a drug, their blood levels of that drug are going to be really low. So again, from a pharmacist perspective, it's important to understand whether a drug uses the, in this case, two to six pathway to become more active or less active, and then based on that and knowing whether a patient is alternative metabolizer or poor metabolizer, or a wild type, normal metabolizer, that helps us understand or better predict how a patient is going to respond to a given therapy. Dr. Khyati Patel 05:51 And here we were talking about the phenotypes, right? Let's, let's kind of reverse the process a little bit and learn about the genotyping, right? So how do we measure this 2d six activity? You know, what are we looking for when we are doing the test? How are we telling one person that you are an ultra metabolizer versus your the wild type metabolizer versus your poor metabolizer? Dr. Sean Kane 06:15 Well, things start with snips. So snips are SNPs, single nucleotide polymorphisms, and this is a way that we actually test someone's DNA to look for a specific variation. So typically, we're saying, okay, at position 13 on the 12th chromosome, is that an A or a G nucleotide? And then, based on that, we can decide whether a patient has or doesn't have a given polymorphism, and one or more of these polymorphisms are associated with what's called a star allele. So usually a star one allele is the normal or the wild type of most common type, and then they just keep numbering. So a star two allele or Star Three allele is going to be some variant or variation that is different than the star one wild type, Dr. Khyati Patel 07:02 and each of these 2D6 star alleles then has the functional categorization right based on how functional it is. And then you attach a sort of like an activity score that goes from zero being no activity to one being the normal activity. Yeah. Dr. Sean Kane 07:21 So a normal allele is going to have an activity score of one, meaning that is a normal functioning similar to wild type. A reduced function allele is going to have an activity score of either point two five or point five, which just means that it's roughly about a quarter to half of the normal activity in terms of how active that enzyme is and then if someone has a no function allele, that's an activity score of zero, which means that they they make the protein that is similar to CYP2D6, but that protein doesn't have any enzymatic activity at all. It has no ability to kind of metabolize off drugs, and therefore it has no activity at all. Dr. Khyati Patel 07:59 And here, Dr. Kane, we're talking about a single copy, right? But we know patients will have at least two of these star alleles, because we're getting one from mom and one from dad. And so do we then just kind of add up this activity scores, Dr. Sean Kane 08:15 we do. So everyone is going to have at least two of these star alleles. So as an example, someone was a star one, the wild type, and they have an activity score of one from that, and they have a, let's say, a star five, which is no function allele. Activity score 01, plus zero is equal to a score of one. So this patient's activity score would be a one. And if you think about it, a normal activity score is two. So you get an activity score of one from mom, assuming that they're wild normal type, and then activity score of one from dad. You add those together, so normal score is two. So anything less than two is going to be a little bit on the lower activity side. Anything more than two is going to be more active. Dr. Khyati Patel 08:57 And I think things get a little confusing when it comes to 2d six, because I learned, and this is new to me, that 2d six can be commonly duplicated or multiply. So patient actually can have more than two star alleles. How does that work? Dr. Kane, Dr. Sean Kane 09:15 yeah, and this is pretty unique to CYP2D6. What happens is the CYP2D6 genome can be duplicated or multiplied on the chromosome itself, which means that instead of having one allele from mom, one allele from dad, one of those alleles can actually be duplicated. This is called a copy number variant. And what that means is that you could actually have three or four star alleles that encodes for this enzyme, so you actually have more copies than a normal human would have. So as an example, someone may have a CYP2D6 star allele, star one, and then a star 2x two. The x2 means that they have two copies of it, so they'll actually have a star one, a star two, and then a second. Star two. Two and that's actually how you can have ultra metabolizer or a patient with an activity score that is more than normal. It's not that the enzymes themselves are just extra good at metabolizing off drug. It's just that they have more enzymes than they normally would because they have multiple copies of that same star allele. Dr. Khyati Patel 10:18 So that's a very interesting discussion on the genotype. But then, when we do a task and we find a patient having certain genotypes related to 2d six, we then assign them a phenotype type based on these activity scores. And as you mentioned, Dr. Kane earlier in the example, you know score of two is considered normal, so an activity score above 2.25 would be considered Ultra metabolizer. And so as imagined this, patients would have, you know, more activity of somebody who would have wild type to the six phenotype. Dr. Sean Kane 10:55 And then we go to normal metabolizers that have an activity score roughly about 1.25 to 2.25 intermediate metabolizers, where it's zero to 1.25 and then finally, poor metabolizers have an activity score of zero, which means that they literally have no 2d six activity in their body, because the star allele that they have does not function enzymatically like a normal, wild type 2d six would do. So they're not going to have any enzymatic activity compared to someone who has a normal, wild type CYP2D6 allele, and Dr. Khyati Patel 11:28 Dr. Kane, just like learning about Warfarin polymorphism, we know there are certain patients that could depend on where their origins are, would have different activity. Are there any variations that we get to see for 2d six phenotype based on where patients are located, where they from? Yeah. Dr. Sean Kane 11:49 So the CPIC guidelines that we're going to discuss in a little bit, they do kind of outline, what are the typical demographics of people who are ultra metabolizers or poor metabolizers when it comes to geography. So Europeans is an example. They're most likely to be poor metabolizers. Where they have that activity score of zero, roughly about 7% of Europeans, or about 8% of Caucasians, are poor metabolizers. In contrast those in Oceania, this is basically Australia, New Zealand area, they're most likely to be ultra rapid metabolizers, and they actually have a pretty high percent with that phenotype of about 20% of that patient population. If you kind of took everyone as a whole, all humans in general, regardless of geography, roughly half of humans have a normal two to six metabolism about a third are intermediate metabolizers, and then mid single digits. So we're talking like 567, 8% are ultra rapid metabolizers, and then low single digits, like one, two, 3% are poor metabolizers. But again, a lot of this depends on bio geographic group in terms of race, ethnicity and geography. Dr. Khyati Patel 13:00 So again, putting it all together in a perspective. You know, if you give a drug to 100 patients, that's metabolized by step 2d, six, you know, some of these patients will metabolize the drug extensively. Some will metabolize it at a normal, late and then some won't metabolize it at all. And you can imagine, as a healthcare provider and a pharmacist, you know this poses a huge variability in in how the drug would respond, right? And that's where kind of knowing these genotypes and phenotypes would come in handy. But what do you do when you don't have this information on hand? Dr. Sean Kane 13:37 Yeah, in actuality, most of the time, most clinicians are not going to know whether a patient has a given phenotype of 2d six. Just as an example, 23andme which is a very common platform for testing, you know, genetic testing at home, they don't currently test for 2d six. And therefore, for the most part, most patients to be able to get 2d six phenotyping. This is going to be done in a lab by a healthcare provider, as opposed to being done by a patient at home just because they want to test and we will talk about CPIC guidelines. So CPIC stands for clinical pharmacogenetics Implementation Consortium. They actually have guidelines for specific drugs and drug classes. The FDA labeling for many drugs actually also contains 2d six phenotype information in terms of what to do if you were to know that. But from my perspective, at least, Dr. Patel, there's a couple of things, even if you don't have 2d six information, that is important for healthcare providers to know about these drugs. One, it is important to know if a drug is heavily metabolized through 2d six, and if it is, it's important for healthcare provider to understand whether that means that if a patient's an ultra rapid metabolizer, as an example, they're going to have very low drug levels or very high drug levels, because it's being activated or inactivated by that pathway. And again, because oftentimes, we don't have 2d six information, just recognition. That there are drugs out there that are going to have a an incredible amount of inter patient variability. So if a patient, for example, has a bad reaction to codeine, as an example, you should not give them Tramadol, because it uses that same two to six pathway, and it's probably going to be a similar pattern, right? Dr. Khyati Patel 15:16 And I think that's kind of lead us to talking specifically about Tramadol and codeine. And as we know, the CPIC guideline exists for these two particular drugs we have reference in the in our show notes if you're interested in checking out the guidelines. But basically, codeine and Tramadol, they're both metabolized to more active metabolite using the CYP enzyme. So codeine it's converted to morphine, and Tramadol is metabolized or converted to O-desmethyltramadol. And these are kind of more active metabolites that exert therapeutic effect, but also can bring toxic effect if it's too much. Dr. Sean Kane 15:57 And the way that they get converted is through that 2d six and the phenotype of a patient with 2d six actually has a huge role in terms of drug levels of these active metabolites. So just to put a number to it, with coding, again, coding gets converted to morphine through 2d six, if someone is a poor metabolizer where they have very, very, very little, if any 2d six activity, their drug levels of morphine, the active metabolite, will literally be 95% lower than someone who has normal 2d six activity. And if someone's an ultra rapid metabolizer, where typically they're going to have multiple extra copies of 2d six, they're going to have 50% higher morphine levels when taking coding compared to a normal metabolizer. So you really run the gambit the spectrum of patients that have basically no response because they make no morphine, and patients that have an exaggerated, almost toxic response because they make too much morphine. And then obviously have everyone in the middle as well. Dr. Khyati Patel 16:56 And so fast forward. These guidelines, actually, you know, do have strong recommendations for both of these drugs when it comes to patients who are ultra rapid metabolizer or poor metabolizer. And so for example, for ultra rapid metabolizer, those guidelines actually says to avoid the use, because patient, again, will convert the drug into more of that potent actin metabolize which could lead to toxicities such as respiratory depression or nausea or projectile vomiting or sedation, etc. And then, same case, you know, if your patient is a poor metabolizer, they're also asking to avoid because the drug won't get to the active component which exerts the therapeutic effect, the analgesia, right? So if you're not going to get there, the drug may be render ineffective at that point. Dr. Sean Kane 17:46 And actually, even if you look at the package insert for coding as an example, coding literally has a boxed warning saying that respiratory depression and death have occurred in children who receive coding following a tonsillectomy or adenoidectomy, and they had evidence of being ultra rapid metabolizers of coding because of 2d six polymorphisms. So it's not just, you know, a theory, literally, children have had respiratory depression and have died because they were rapid metabolizers and converted too much coding to morphine and had a side effect from essentially a morphine overdose caused by too much of that 2d six activity. Dr. Khyati Patel 18:26 And, you know, as we're talking about, you know, both of these agents, kind of in the opioid category. There are other opioids, like the hydrocodone, which is part of Norco and oxycodone, which is part of Percocet. They do utilize two disease activation. So this variation would be pertinent to them too. However, this isn't the only pathway that they're using to get activated, and so we're not seeing more clinical impact on these drugs as efficacy and safety. When your patient does have these, you know, different phenotypes with the 2d six enzyme. Dr. Sean Kane 19:03 And as we mentioned, Dr. Patel, 99.9% of the time a clinician is not going to know whether a patient has a given phenotype of 2d six because testing is not common. So with that in mind, if you're a clinician, you have a couple options. One is just don't use codeine, and probably don't use Tramadol, because you recognize that there is a a pretty good probability that you're going to encounter someone who's a poor metabolizer. Will get no effects, or ultra rapid metabolizer, you're going to get side effects from too much activation, and maybe pick something different, like Norco with hydrocodone, or Percocet with oxycodone, or just recognize that when you prescribe these medications, that you're going to see a lot of variability, and some patients are going to be more sensitive, and some people are going to be less sensitive, and if they have kind of a bad side effect or a lack of effectiveness, you don't go to the other one. So if they if codeine doesn't work, you don't go to Tramadol. Because it uses the same pathway, and one would presume that that pathway is compromised for that individual, right? Dr. Khyati Patel 20:06 And then that with that, you know, you would apply either closer monitoring or more patient education to, you know, watch out for those things. And I think you know, to some degree, a good medication history taking goes a long way as well. And so if you know, in your medication history process, a patient says, you know, oh no, they use codeine. It didn't work for me. Listen to that, right? Listen to that. Or if they may say, Oh yes, I got codeine. And I just met my I had terrible stomach side effects and stuff. Listen to that. And maybe don't use Tramadol. That's just say, for using the same pathway. Dr. Sean Kane 20:43 So Dr. Patel, the other really notable example of a drug class that uses two to six are a variety of antidepressants. And what's interesting here is that we see both ways. So certain antidepressants are pro drugs that get activated to an active metabolite, but actually most of the antidepressants get metabolized, and the body gets rid of that drug through 2d syncs. Dr. Khyati Patel 21:06 And here too we have the ultra metabolizers. Again. They will metabolize certain antidepressants too quickly, and so they're not going to render the antidepressive effects due to the low blood levels of them. And patients may have you know, patients may be poor metabolizers, so they will metabolize certain antidepressants too slowly, leading to accumulation of these agents in their in the blood stream, and rendering more side effects that patients may experience. Dr. Sean Kane 21:36 And this is actually a fairly new or Hot Topic Dr. Patel, because the C pick guidelines just updated in April 2023, for antidepressants. So SSRIs, SNRIs, tricyclic antidepressants. So we're going to cover a little bit of what's in those new guidelines. But for the listeners that want to read more about this, a reference is available in our show notes, Dr. Khyati Patel 21:58 and we have, you know, many different classes of antidepressants. So just going by class by class, SSRIs, particularly one that is affected by the CYP2D6 pathway is our paroxetine. Brand name is Paxil. The other SSRIs are impacted by your CYP enzyme variation, but not CYP2D6, that's CYP2C19, and that's, you know, separate guidelines altogether, but focusing on CYP2D6, paroxetine, Paxil is the one that's impacted Dr. Sean Kane 22:27 when it comes to SNRIs, this is the one where it's a little bit different than the other antidepressants. So in this case, venlafaxine, or Effexor, which is an SNRI, is actually the opposite of our other antidepressants. So it does have an active metabolite, and the way that venlafaxine gets converted to its active metabolite is through CYP2D6 activation. So with other antidepressants, CYP2D6 gets rid of the drug. In this case, CYP2D6 activates venlafaxine to its active compound that exerts its antidepressant effect. So in that case, we'll see the opposite clinical effects. So if you are an ultra rapid metabolizer, you're going to make a lot more of that active metabolite and potentially get toxicities from too much drug level in your blood. And interestingly, other SNRIs are not heavily impacted by CYP2D6. So this is really a venlafaxine unique quality within the SNRIs. Dr. Khyati Patel 23:21 And then last but not the least, we have the tricyclic antidepressants such as amitriptyline or nortriptyline (Pamelor). And there is a few others. And technically, all of the TCAs are impacted, but the majority of our clinical data is with amitriptyline and nortriptyline, and Dr. Sean Kane 23:40 in that case, just like with our SSRI of Paroxetine 2d six is responsible for getting rid of these compounds. So again, if you're a poor metabolizer, as an example, you're going to hold on to the TCS longer and be more prone to more side effects. Or if you're an ultra rapid metabolize you're going to get rid of the TCA too quickly, then you're going to have inappropriately low blood levels and a lack of effectiveness. Dr. Khyati Patel 24:07 And so again, kind of reading through the newly published guidelines, there are some recommendations laid out for patients who are either Ultra or poor metabolizers of 2d six, and the CPIC says for ultra rapid metabolizer patients do avoid the antidepressants that are impacted by this, because, again, it's not gonna, you know, have enough efficacy. There is, however, no recommendation about when the vaccine, Dr. Kane, you mentioned about how it's a little bit different, where we actually need 2d six to activate the drug. And I think that's probably because of we don't have enough clinical outcomes data, and you know, we are going to potentially see increase in the risk of toxicity as well. Dr. Sean Kane 24:50 And then for those poor metabolizers, the CPIC guidelines recommend a 50% dose reduction, or just avoid use among these antidepressants that use CYP2D6, and again, the rationale for these other antidepressants, besides venlafaxine, is that you're going to have more side effects because you're not going to get rid of the drug as quickly. But when it comes to venlafaxine, for those more poor metabolizers, the CPIC guidelines do recommend that you avoid its use, because you're not going to be able to activate the venlafaxine to its active metabolite as readily and you're probably not going to see as good of an effect. So in this case, they do recommend avoiding venlafaxine use as a stronger recommendation than for those that are ultra rapid metabolizers. Dr. Khyati Patel 25:32 But the problem here Dr. Kane is the same as we discussed with codeine and Tramadol, is that most patient we won't have information about their 2d six genotyping, or, you know, their metabolizing capacity, the phenotype. So how do we go about choosing certain antidepressants in this case? Dr. Sean Kane 25:52 Well, one thought is, maybe you avoid some of these therapies specifically because you're concerned about 2d six variability. So with paroxetine as an example, this is not one of the more common SSRIs that are prescribed on the market. It does, aside from its 2d six variability issue, it's more sedating. Has a shorter Half Life. Patients are more likely to have withdrawal symptoms with paroxetine. So there are other reasons why maybe you wouldn't pick paroxetine anyway. This is just another reason, on top of all of those reasons, why maybe other SSRIs could be selected instead. Dr. Khyati Patel 26:27 But then, as we discussed earlier, those other SSRIs like citalopram, escitalopram, sertraline or fluoxetine, are impacted by CYP2C19 genetic variation. So that's another topic for another day. But you know, you go from one direction, you follow it, you know, in a plot twist, anyways. Dr. Sean Kane 26:47 And when it comes to the tricyclic antidepressants, certainly we shouldn't be using these as first line therapies anyway. For anxiety or depression, they're mostly used at this point in time. For neuropathic pain has plenty of anticholinergic side effects associated with them that we should be aware of anyway. So there's a lot of reasons to try to avoid these if you can. And if you get to that point and you have to consider them anyway, you're probably just going to use them with the recognition that some patients are either going to be kind of the ultra rapid metabolizers, where they're going to get rid of the TCA too quickly and have very little efficacy, some patients are going to hold on to it for a longer period of time and have more toxicity. So it's, again, more recognition that if you're going to pick a TCA, that you do need to monitor these patients and kind of educate them that they could be really sensitive or have very little effectiveness from the medication. Dr. Khyati Patel 27:37 And then same goes with on the vaccine. You know, aside from it being a little bit different, and how it's impacted by this 2d six variations. We know that norepinephrine reuptake efficacy is dose dependent. So at lower doses, it's kind of like an SSRI. You know, you need kind of higher doses to act more like an SNRI. So really, you have lot of these variations, but other factors that are pertaining to these antidepressants to consider and picking the right therapy for your patient. And Dr Dr. Sean Kane 28:11 Mattel, I like that you mentioned that because when it comes to pharmacogenomics, you know that is one component of a multitude of components that we think about when we think about pharmacotherapy and picking the best agent for a patient, you know 2d six pathway is also susceptible to drug interactions, so there are some drugs that make it so 2d six doesn't work as well as it normally would, regardless of a patient's genetics or even picking the Right therapy because of renal function, obesity, hepatic function, disease, state considerations. There's so many other things that we also consider. This is one of the multitude of things that we think about when we're thinking about the best therapy for a given patient, Dr. Khyati Patel 28:53 100% and you know, as we kind of alluded in the beginning of the episode too, is that, you know, these particular drugs that we talked about has the CPIC guidelines, but there are other other therapeutic areas where the variation in CYP2D6 is clinically significant. So some examples, you know, are beta blockers, like Metoprolol, Carvedilol or propranolol, are impacted by this, where your Metoprolol, for example, the poor 2d six metabolizers were going to have several fold increase blood levels that could result into things such as low blood pressure or heart rate, dizziness, you know, all that kind of equally Dr. Sean Kane 29:37 and again. Dr. Patel in the case of Metoprolol, this isn't just some edge case consideration in terms of it's not widely known. 2d six metabolism and polymorphisms is literally described in the package insert for Metoprolol that there are some patients that are going to be very sensitive to Metoprolol because of being poor 2d six metabolizers. So this made it into the package and. Or in terms of a thing that clinicians should be aware of, even if you don't actually know patients two to six phenotype. Dr. Khyati Patel 30:08 The other examples are, you know, a lot of our 5‑HT3 antiemetics, like one example is ondansetron or Zofran. Again, we do have CPIC guidelines available for this particular drug class. And again, these ultra metabolizers are going to get rid of ondansetron too quickly. And so when they take ondansetron, they're not going to have the beneficial effects for preventing, or, you know, treating nausea. However, the exception to this drug class is granisetron (Kytril) that doesn't rely on the CYP2D6. And so if you do know a patient is an ultra metabolizer of CYP2D6 and they need an antiemetic from this class, that would be the one to go with. Dr. Sean Kane 30:54 As we mentioned, 20 to 25% of drugs on the market utilize 2d six in some form or fashion. There's plenty of other examples out there where 2d six metabolism is really relevant. So Bupropion, or Wellbutrin Zyban, is another example. We actually covered this in HelixTalk episode 160 where we talked about how Bupropion actually blocks the 2d six pathway to increase drug levels of dextromethorphaned So it's both metabolized by 2d six, but also inhibits that pathway. Other examples are Dextroamphetamine or amphetamine or Adderall, certain atypical antipsychotics like arapiprazole or Abilify, Risperidone or Risperdal. We have an agent called donepezil or Aricept for Alzheimer's disease and tamsulosin or Flomax for benign prostatic hypertrophy or BPH. And again, we're just scratching the surface. There are so many other drugs that use the 2d six pathway, we only have C pick guidelines for a handful of them, and sometimes they're mentioned in the package insert as 2d six interactions, or 2d six variations can impact the disposition of a drug, and we're probably going to know a lot more in the next five to 10 years, as we do more genetic testing and have more data on whether a certain phenotype actually have a clinically relevant difference when it comes to a drug disposition in the human body. So Dr. Patel, again, one take home point that I want all listeners to understand from today's episode is that 2d six is actually a pretty common pathway for drug metabolism. 20 to 25% of drugs on the market go through 2d six, and there's a huge amount of inter patient variability with 2d six metabolism ranging from ultra rapid metabolizers all the way down to poor metabolizers. And this has a huge impact on drug disposition Dr. Khyati Patel 32:40 and drugs that heavily rely on CYP2D6 metabolism are going to have variability in clinical response. So drugs that rely on, you know, metabolic inactivation of CYP2D6, and the other drugs that you know, use this enzyme to become and convert into more potent, active compound. And so that's where the variabilities are going to come Dr. Sean Kane 33:06 in from. And in the case of opioid analgesics, we have a lot of data about codeine and Tramadol that heavily rely on the CYP2D6 activation pathway, and that activates these opioids to a more potent opioid compound. So if someone has too much CYP2D6 activity, they'll make too much of these active compounds, and they'll get side effects and toxicities. Or if a patient has very low CYP2D6 activity, they're going to have very little therapeutic effect, because they're not going to make very much of the active metabolite. Dr. Khyati Patel 33:38 And similarly, numerous antidepressants, we're talking paroxetine, nearly all TCAS, tricyclic antidepressants and venlafaxine, they rely on CYP2D6 metabolism, and the differences in this CYP2D6 metabolism are going to either have toxicity issues or lack of efficacy issues when you're using these medications Dr. Sean Kane 34:02 for the listeners, if you'd like to dive in a little bit deeper, we have a number of references in our show notes. Again, our website's on pause right now, but you can see the show notes in your podcasting app, and the show notes will be available on our website in early July, but you'll see a review article about pharmacogenomics of commonly prescribed medications, and then some of the C pick guidelines, about 2d six phenotyping, about two to six metabolism with opioids and 2d six metabolism with antidepressants. Again, that one that was just recently published. So I think that wraps up today's episode quite nicely. Dr. Patel, for the listeners, we love the five star reviews in iTunes, so keep those coming. If you have any requests in terms of what you'd like to hear more of please contact us. Our contact information is available on our website at HelixTalk.com so with that, I'm Dr Dr. Khyati Patel 34:49 King and I'm Dr. Patel, and thank you for listening. Study hard Narrator - Dr. Abel 34:54 if you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star. Review in the iTunes Store, search for HelixTalk and place your review there to Narrator - ? 35:05 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.