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Your cheat sheet on... NFT bear market

NFT space may seem like a jigsaw puzzle. NFT Cheats is a series of newsletters that helps you put the pieces together.
NFT Cheats by Rarible is a newsletter that explores the very pillars the NFT space stands on. Think of those as the NFT World-bearing turtles (or Apes).
It’s called NFT Cheats because each newsletter is designed as a cheat sheet that brings you up to speed on a given niche within the NFT space.
NFT bear market is the third subject in the series. The previous issues covered Historical NFTs and NFT Security. To put together a cheat sheet on today’s topic, we talked to wale.swoosh, researcher-in-residence at Azuki and a self-described ‘Director of Threads’ on NFT Twitter.
Wale got into NFTs in early 2021 after hearing about them on Gary Vee’s Instagram. He joined Twitter a few months after that to become a better trader as he realized that NFT Twitter plays a big role in that. Wale quickly fell in love with the community, and started sharing his own thoughts on the timeline, quickly becoming one of the most popular NFT content writers known for his in-depth threads.
DO NOT treat any of the information below as financial advice, and do your own research (DYOR) before buying into any asset.
The interview has been edited and condensed, meaning the content below is attributed to the guest expert, but shouldn’t be treated as a direct quote.

What does a bear market mean for NFTs?

A bear market in Web3 is usually marked by a general flattening of interest in the space. Fewer new people join, and some people who were in Web3 leave.
That leads to a crash in prices, teams stop developing, and the sentiment in the space is generally bad because everyone is fighting for the crumbs of a shrinking pie.
If you look at it historically, bear markets are always caused by an external macro influence. We’ve had several bear markets in crypto since the industry emerged, and this seems to be the first major bear market for NFTs specifically since they hit the mainstream in 2021.
The current bear market started around Q2 2022, and of course we just can’t know when it will end exactly. But I'm positive that it will be followed by a bull cycle.
During this bear market, we’ve seen projects shed around 70-90% of their floor prices. At this point, it might be hard to believe that certain NFTs were trading at 3-10x their current floor price.
Moonbirds' historical floor price, as shown by NFTpricefloor.com
There are several reasons behind that grand fall. First, a lot of people have simply left the space. According to recent numbers, there are around 7,000 active traders left. When you have a few thousand people creating and trading maybe millions of NFTs… the supply/demand ratio gets crazy. When the demand is low, the floor price will follow.
Projects themselves also play a role in this. Without naming any specific ones, we have many teams that have made major strategic mistakes in recent months. In fact, I don't think there are blue chips anymore in the space, outside of the top 3-4 most successful collections.
Then we had ETH volatility, the memecoin season, Blur experimenting with some trading mechanics — all of that have also not been good for the floor prices across the board.
The most important thing for the NFT space at the moment is to get more people in, because when you have 7k traders, it's really hard to run a successful project. Right now, holders are basically playing hot potato with each other. As to how we might onboard more people — that's a whole other topic.

NFTs are dead. Long live NFTs!

People who say NFTs are dead are partly right.
Most projects are indeed dead or are in the process of dying. 99% of them won't come out of this bear market because they just don't have what it takes. Those who will come out, however, will come out stronger.
Having said that, NFTs as a technology will never ever die because it brings so much innovation to areas like gaming and digital ownership, for example.

Metas, or why there's always a "shiny thing" in NFTs

To better understand the nature of the NFT market, it's useful to understand the role metas play in it.
Meta is a certain pattern that we see emerge (most of the time suddenly) and disappear (that also tends to happen quite quickly) in the NFT space.
A meta can last anywhere from a few days to months. A good example would be the open edition meta we saw a few months ago started by Jack Butcher’s Checks. Once it became clear that Checks are doing good, we saw all those other projects doing open editions, mostly following the same pattern/concept…
At the time, the majority of the content on the NFT Twitter timeline was about open editions. Initially, when a new meta emerges, it starts to generate/feed off hype— everyone wants to be a part of this new exciting thing, and ultimately make some money from it (be it trading, engagement farming, or both).
It’s hard to put a finger on what exactly makes a meta pop off, but once it gets going, it spreads fast.
Wale's thread on metas (click on the pic to read)
You have to realize that sooner or later, every meta always disappears. The people who are invested in it often think (or want you to think) that it’s here forever, but in reality there's always the next shiny thing a few weeks later that people will go chasing after, forgetting about the one that preceded it.
That being said, the OG projects that start metas—like Checks, for example—often keep at least some of their relevance, while most other unoriginal projects who were just trying to copy them vanish.
Besides metas, there’s also culture. Culture is a more fundamental kind of thing. Sometimes it's hard to differentiate: is this new thing more transitory and based on short-term attention, or is it here to actually stay, setting a new standard for the space for years to come?
There weren’t many events that actually revolutionized the industry, like what Yuga Labs did when they airdropped the serums for the MAYC collection, the distribution trick many projects adapted later on. But those usually come around in a more subtle manner.
So normally when every week you have people saying “oh, that's the new thing, it will change the space forever for years to come” and are super vocal about it, it’s almost never the case.
The attention span in this space is incredibly short, and people tend to put most of their attention into things that are ‘meta’ at the moment.
Will traditional brands kick off the next bull?
There are a few examples of traditional brands doing a good job with their web3 initiatives, Gucci and Adidas specifically come to mind. But you and I would probably have a hard time naming 10 successful web2 companies who came into the web3 space, so we haven't seen that unfold just yet.
When it comes to getting new people into NFTs, major brands could be one way to do it — when people see a trusted brand, they might want to get involved, as they’re more likely to trust a brand they already know.
It’s a two-way street: when more people in general will get interested in NFTs, web2 brands will likely have an easier time onboarding people as well.
It also depends on which audience the specific brand wants to address. When you want to get into the hardcore NFT community, you better understand web3 culture and be part of it so your activation doesn't feel forced—the infamous Pepsi and Budweiser exchange on Twitter became a meme for a reason. But at the same time, as more legacy brands will come in, the focus might shift away from the core NFT community to retail users.
And when more retail comes in and NFT becomes more adopted as a technology, it is likely that the end user won’t realize that they are interacting with the blockchain or even that they’re buying an NFT. It will be more subtle, and the majority of retail users probably won't be creating wallets and trading NFTs on OpenSea/BluRarible per se.
Nike’s .swoosh is another good example of a web2 x web3 crossover—when you sign up there, you don't even know that you are minting an NFT. I think that's a good approach to bringing more people in, because right now the blockchain infrastructure is still very complicated for new people.
At the moment, if you know nothing about web3, blockchain or crypto in general, the learning curve is just too steep: you have to go through the process of creating your own wallet and writing down a 24-word seed phrase, buying and swapping tokens, sometimes bridging—all that just to get an NFT you want. So in regards to mainstream adoption, it will be crucial to build platforms, infrastructure and tools that will be intuitive even for people who are not crypto NFT natives.
Is it a good time to enter the NFT space?
It's a good time to take your time.
Let’s be honest: If you’re coming into the NFT space right now, there's a very high chance that you will immediately leave. The bear market vibes are really difficult to handle for a newcomer.
When you go on NFT Twitter these days, there’s so much toxicity, shilling and hate going on… It's really terrible. Then you have short term metas where some people make money and tweet about it nonstop while the silent majority loses money. Of course if you're a newcomer and most of your timeline is talking about how this thing is pumping and they’ve already made 100x on it, you’ll want to join in. The meta will then move on, and most likely you’ll lose money. I think that's driving a lot of people away from our space.
But a bear market is actually a great opportunity to learn about NFTs. For me, the ideal way to start in the NFT space is to make a Twitter account, and get involved in NFT Twitter by following some trusted people and just spending time reading their takes, maybe participating in some discussion. And then when you feel comfortable about what you know and feel like you can make informed decisions, then maybe start buying your first NFT or minting your first NFTs (always with the money you can afford to lose).
Rarible Bear Pass, the free open edition mint that generated 683.5k copies
As for choosing which projects to join, I recommend looking at the team behind it. That’s what it is all about in Web 3. When you have a team that's emerged into the space and is actually building for the community, that's a massive green flag. Invest in people you personally believe in. To me, the team is way more important than the art/roadmap because if you don't have a team that's able to execute, you can have the best roadmap but the project won't be successful.
But please remember that in web3 it can all change within weeks or even days. This space is moving extremely fast, and that hasn’t changed even during the bear market.
And if you're already in the NFT space, it’s a good time to build. When you have a project is a good time to build in silence so you are ready for the next bull market—and I am positive that it will happen.
5 people to follow to learn more about the NFT market ️

• Elena (@ElenaaETH)
  
• Alex is Building (@AlexIsBuilding)
  
• Legendary (@Legendary_NFT
  
• NFTboi (@nftboi_)
  
• zaimiri (@zamirii)
  

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Hello and welcome back to SAR! First off, I apologize for the hiatus in blog posts but had some things pop up and now I am clear! Alright off to the good stuff: For most things in life there are few reasons why one person of a particular sex or race would be more well suited to a particular job than another person of a different sex or race. Afterall, the quality of a cup of coffee would be just the same from a Black female barista with 10 years of experience as an Asian male barista with 10 years of experience. But medicine is a bit different; we do see differences because of sex or race that are important to understand, acknowledge, and factor into the diagnosis. Obviously a male isn’t going to have pregnancy on the differential diagnosis and prostate cancer isn’t a factor for female patients. The differences in Pharmacokinetics and Pharmacodynamics of a drug, a disease, or treatment can vary wildly between the sexes or between races. So today I want to look at the differences that we are only now starting to realize and the emerging role of Pharmacogenomics as the next horizon for medicine. So the big question is: you got something big in your genes or are you just happy to see me? :P
Disclaimer: this post is not designed to be medical advice. It is merely a look at the chemistry of medications and their general effect on the body. Each person responds differently to therapy. Please talk to your doctor about starting, stopping, or changing medical treatment.

Pharmaco—what?

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Because I am a pharmacist I want to center our discussion on the drug choices and attributes influenced by sex and race but in order to do that we have to lay a foundation. The processes that move drugs from a pill into your body are broadly referred to as ADME but there is a hidden L step that is just as important to talk about as well. The lifecycle of a drug, LADME, are the five major processes that affect a drug inside the body. Let’s look:

1. Liberation - When you swallow a tablet, the pill as a whole isn’t magically absorbed through the intestinal wall, it has to break down and liberate the drug from the dosage form. Liberation is the process of how the vehicle (what the drug is administered as) is broken down so the drug is free floating inside the body. This is also where we can see differences in timing such as extended release or immediate release products. It also governs other forms too like tablets you can chew or patches you apply onto the skin.
2. Absorption - Now that the drug has left the tablet, it needs to move from the GI tract space into the body proper. The mucous membranes inside the intestine have a HUGE surface area allowing for many substances to be absorbed quickly and efficiently. How well a drug is absorbed plays a major factor in how well the drug’s action is. What if you're administering an oral (PO) antibiotic but the patient has diarrhea and they move the drug too quickly through the intestines? Can we be sure it was all absorbed? This is why we have alternative administration pathways like intramuscularly (IM), subcutaneous (SubQ), intravenous (IV), rectally (PR), vaginally (PV), optically (OU), and more. Each gets the drug inside the bloodstream where it can then get to the place it needs to go.
3. Distribution - Speaking of getting where it needs to go, we have distribution. Once the drug is absorbed and dumped into the bloodstream, it needs to go to the place where the receptor, channel, or structure is for it to have action. Some places are easier to get to like highly vascularized (lots of blood vessels) areas like skin, the liver, and kidney while others are a bit harder such as the heart tissue, lungs, and brain.

• “How does the drug know where to go?” It doesn’t! It will go everywhere in the body but that doesn’t mean that it will have action there. One good example is with Carbidopa, a dopamine receptor agonist used for Parkinson’s (oh look a post!). When a person take’s Carbidopa orally, it's absorbed into the blood and starts to distribute throughout the body generally. We want it to go to the brain to alleviate Parkinson's symptoms but it can also activate dopamine receptors in the periphery where it causes dizziness and constipation (I highly recommend reading the post if you want to learn how).

1. Metabolism - Eventually the drug has to leave the body and metabolism is the first step in that process. Metabolism has two phases: phase 1 is responsible for deactivating the drug by modifying the structure of the drug in a way where it cannot fit inside the receptor anymore. Phase 2 takes the deactivated drug and makes it very water soluble so that it can leave the body extremely easily. The rate of metabolism is dependent on many different factors and is highly specific to each person which is why we do large pharmacokinetic studies in drugs before they are ready to be on the market. Failure to understand how a drug is metabolized can lead to toxicities from drug accumulation OR give too little a dose because the drug is metabolized so quickly.

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5. Elimination - The last step in the drug lifecycle is elimination or how it physically gets out of the body. The majority of drugs leave via urine of which the kidney is responsible for that process. Having a working kidney is key for correctly dosing a drug because an underworking kidney may not eliminate the metabolized drug fast enough causing it to accumulate. There are other pathways too; fecal excretion (through biliary elimination) is another major route but some drugs can be eliminated via the lungs (such as alcohol, which is why it can be detected in a breathalyzer), through breast milk (which is why understanding drugs in pregnancy is SUPER important), sweat, saliva, and sebum.
Obviously there are major differences in LADME between males and females—after all it's hard to insert a drug vaginally in a male. But now that we have a general idea of what the drug is going to be doing, let’s dive into each section and talk about the sexual and racial differences we see at each step.

Liberation—”Liberty, equality, fraternity, or death; - the last, much the easiest to bestow, O Guillotine!”

When we think of liberation I want you to think of two things: getting the drug out of the formulation (such as the tablet or capsule breaking down in the stomach) and where that breakdown happens. These two factors are hugely important when we think about how the drug will eventually get absorbed—after all if you can’t liberate the drug correctly then there is no chance that it will be absorbed and then be utilized by the body. First let's talk about formulations:
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• In your daily life you’ve probably come across different formulations of drugs. Here we are going to look at the most basic of them: Immediate Release (IR), Delayed Release (SR), and Controlled Release (CR) also known as Extended Release (ER). The main differences between these different forms is how quickly the tablet moves from a solid lump sitting in your stomach to dissolved particles. The slower it releases then the slower the drug dissolves into your stomach and the slower it will eventually get absorbed. Initially all drugs were formulated as Immediate Release because we had little understanding of the utility of longer dosing formulations as well as we didn’t have the technology to do it. There are a whole bunch of different types of Extended Release types each with different uses and drawbacks and choosing which is best for your drug is extremely important for deciding what works best. At the end of this section is a diagram that shows all the different kinds of formulations.

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• But for now I want us to focus on the graph of drug liberation curves. The graph is divided into three zones with two very important barrier points: the Minimum Effective Level (MEL, aka MEC) and the Minimum Toxic Level (MTL aka MTC). Essentially if the curve of the line, representing the concentration of the drug in the body, is below the Minimum Effective Level then there isn’t enough drug to exert its action and we have Subtherapeutic levels in the body. Over time, the tablet dissolves more and more and the concentration continues to rise more and more and we pass the MEL into the Therapeutic Window where we see the action of the drug. In general we can say the higher you are in the Therapeutic Window, the greater the therapeutic effect there is or in other terms, the higher the dose the bigger the effect. Finally if you go above the Therapeutic Window you pass through the Minimum Toxic Level and enter into drug toxicity levels. Now, toxicity is a bit of a harsh word because this doesn’t mean we are going to see death but rather side effects due to too great of an effect of the drug. For example, say you are taking a drug that lowers blood pressure but due to changes in the tablet liberation the concentration rises above the MTL and your blood pressure drops a little too much and you get dizzy.

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• In the first graph we can see how drug design impacts the speed of liberation. Let’s say that we have 100mg of a drug that we are trying to put in the body. Using an Immediate Release formulation would result in a much quicker liberation and thus absorption into the body but we can see that it peaks very quickly and then drops off very quickly. So you may only get a few hours of usefulness out of the drug. Compare this to the Controlled Release system which peaks much slower but also declines much slower too, remaining much more Therapeutic for a longer period of time. We can see this in Adderall used for ADHD—most people will take an Extended Release (ER) formulation in the morning so that they get many hours of sustained therapeutic benefit while they are at school or at work. You can see one method of how the beads inside the Adderall capsule are made—called Pelletization. Essentially an inert core is layered with different chemicals/drugs to build an “Onion” of layers [insert Shrek reference].
  • So wouldn’t extended release always be better because we avoid the toxic levels of a drug? Not necessarily. To give an example of one of my patients, this person was a 911 operator who would take their Adderall XR every morning at 8:30am and work from 9am to 6pm every day. For them, their Adderall would start to wear off at 4pm, so they would get 7 hours of benefit. But what abouts the last two hours of the work day? They can’t be distracted in their job else it costs lives and taking another Adderall XR would mean they are wired until 11pm. No good. This is where the utility of IR formulations come in—this person can take an IR dose at 4pm when the Extended Release starts to wear off and boost their levels back into the therapeutic range and get 3 or 4 hours of benefit but have it be gone by the time they go to bed.

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• So hopefully you can see the utility of choosing different release systems now, but what about the second point: liberating in the right place in the body. Well some drugs are more effective if they are absorbed later in the digestive tract where it is less acidic versus the stomach. So some drugs may have better absorption if we can release them further towards the intestines than immediately dumping them into the stomach for absorption. This is where the utility of Delayed Release (DR) systems comes in. Drugs that are considered Acid Labile or sensitive to acid else they degrade are preserved better if they can liberate from the tablet in a less acidic environment. A great example of this is Omeprazole (Prilosec) which is used for decreasing the production of stomach acid to treat acid reflux or GERD—problem is that Omeprazole itself is very Acid Labile and if it enters the stomach unprotected then it degrades fairly quickly. This leads to the use of Omeprazole DR formulations where it is coated in substances that resist acid breakdown like Shellac or Sodium Alginate, thus allowing for the Omeprazole to be liberated in the small intestine where it is more likely to be absorbed.

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• This is all well and good but how does this relate to sex and race? Well one of the major differences between males and females is that females have a more acidic stomach than males making their stomach environment much more acidic. In addition the Gastric Emptying Time, or how long it takes for substances to move from the stomach into the small intestine for absorption, is significantly longer in females. These two factors mean that females taking a drug that is Acid Labile are more susceptible to degradation in a female than in a male. This means the utility of an Enteric Coated drug which would resist stomach acid would be much more beneficial in a female than in a male. Let’s look at a specific example: the drug Carbidopa is used in Parkison’s to treat the tremors associated with the disease. In younger females, the peak blood concentration for Carbidopa is 22 minutes later than males of the same age. As a female ages and goes through menopause that time to peak becomes more and more similar to males meaning not only are we seeing variability in sex but also in age.
  • Another example is looking at the effect of a drug's natural acidity with the relative acidity of that person. Ketorolac (Ketorol) is a non-opioid pain medication used for moderate-severe pain in people where an opiate may not be preferred. The problem with Ketorolac is that it is extremely acidic naturally and it can cause ulceration of the stomach lining if someone has a very acidic stomach environment like a diet filled with acidic food. What we find is that males can have a Ketorolac dose 36% times higher than females because their stomachs are naturally less acidic meaning that they can handle a more acidic drug without the negative side effects like acid reflux or ulceration.
  • On a racial standpoint we see similar outcomes. It is reported that individuals of Asian descent have a lower acid output compared to Occidental patients. Part of this can be related to the relative smaller body habitus (weight and height) in the Asian population but there is also a decreased expression of acid-producing tissues in the Asian population than other races. When quantified it appears that Asians have about 60% the acid secretion of Caucasians which is a clinically significant difference when considering drugs that need a more basic environment. For example, Levothyroxine (Synthroid) is taken one hour before breakfast because we want the least acidic environment possible, which happens when the body has no food in it. What we find is that Asian populations need up to 55% smaller doses of Levothyroxine compared to non-Asians. Kinda interesting eh?

Is that a polymorphism in your pocket?

Originally I was going to look at each part of LADME individually but kept running into a problem when trying to separate the drug processes into silos. While Liberation is distinct from the rest of the process, ADME cannot really be separated into its components in a way where I can tell the story efficiently. As such we will focus on the poster drugs that are significantly affected by race and sex and then talk about the larger implications in therapeutic development. Now clearly there are drugs that are used in one sex over another, for instance you aren’t going to find Atosiban used to delay labor in a male or Sildenafil (Viagra) for erectile dysfunction in a female. Now that being said they do have other uses but you get the point—so if I talk about a drug please know that I may be talking about a specific indication as well. So with that in mind, let’s jump in!
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BiDil finds a home among Black patients—Hypertension, or high blood pressure, is one of the most common conditions across all races and sexes and is usually referred to as the “Silent Killer” because, well, it doesn’t hurt. Unlike liver failure or an infection, you won’t really see any symptoms of high blood pressure but after a decade of not treating it people do develop critical end organ damage: heart failure, kidney damage, liver damage, etc. Imagine that your veins are like a garden hose; if you put your thumb over the end of the hose the velocity of the water coming out of the hose increases meaning that there is more force. So if you have higher blood pressure, you have higher force hitting your organs. So the medical community has developed countless ways of lowering blood pressure to help save our organs and we can group those medications into a couple categories.

• For the majority of the population we follow a pretty tried and tested protocol of drugs: first up we would use Diuretics which physically decrease the amount of fluid that is in the blood vessel. In the hose analogy this is like if you had a leak halfway up the hose lowering the amount of water exiting the hose at the end. Now there are dozens of diuretics but most people are familiar with Furosemide (Lasix) and how it makes people urinate more (y’know, to get rid of the fluid). If someone needs another agent we turn to drugs like the Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARBs). The ACEs (like Lisinopril, Enalapril, or Benazepril) and ARBs (Valsartan, Olmesartan, etc.) work by inhibiting the ability for a protein, Angiotensin, from connecting with the blood vessel wall. Angiotensin’s main job is to make the blood vessel smaller which would increase blood pressure—these drugs inhibit the action of Angiotensin thus preventing it from raising blood pressure. And our final category are drugs acting on the heart: Calcium Channel Blockers or Beta Blockers. While generally more helpful in situations like heart failure than hypertension, these drugs slow down the heart’s ability to pump blood which then lowers the force that the blood is acting on the blood vessels and organs. In a way it's like turning the faucet on the garden hose letting out less water into the hose.
  • So to summarize, the majority of people will benefit most from a Diuretic (which lowers the amount of fluid in the blood vessel), an ACEi or ARB (which prevents the blood vessels from getting smaller), and/or a CCB or BB (which lower the output of the heart).

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Hydralazine vs Isosorbide Mononitrate

• Enter the Venous Dilators which work by directly expanding the blood vessel size. These drugs are normally used in situations where the blood vessel is obstructed, such as during a heart attack or stroke, due to a clot. Administering a Venous Dilator would expand the blood vessel allowing the blood to wiggle around the clot and relieve the symptoms of the heart attack or stroke. Two of these drugs are Hydralazine and Isosorbide Dinitrate which are used by all sexes and races to prevent the progression of a heart attack and stroke which have very good success. Both of these drugs are fairly old: Isosorbide Dinitrate was discovered in 1949 while Hydralazine was discovered in 1949 and showed fairly good efficacy for decades.
  • Enter two doctors, Jay Cohn and Peter Carson, who wanted to market a new combination drug Hydralazine/Isosorbide Dinitrate (BiDil) in 1989 for congestive heart failure. The FDA said sure, go do a trial and so the duo set out to prove that BiDil was a good option for the general population. They tested their combination in a trial called Vasodilator-Heart Failure Trial (V-HeFT) against the gold standard Enalapril (ACEi) and found that BiDil was…bad. Like really bad, in fact they had to stop the trial early because it would have been unethical to keep people on the BiDil rather than on the known treatment. So V-HeFT didn’t show that BiDil was a good option for the general population except among one subpopulation: Black patients. When you look at the use of Enalapril (and other ACEi) in Black patients we find that the efficacy is quite low. As it turns out, people of African descent have a lower response to drugs like ACEi and ARBs compared to non-Africans meaning that they are worse options for a Black person. So a patient that wasn’t responding well to a Diuretic and needed a second agent would get little help from an ACE/ARB drug. And at this point in time there were no CCB or BB!

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• So Cohn and Carson’s drug application for BiDil was rejected in 1997 because the statistical analysis in their multi-racial study was quite bad. On the recommendation of one of the FDA’s advisory committees they stratified the data on racial lines and discovered a significant difference in response among Africans vs non-Africans. They started a new trial and enrolled 1050 African men and women showing a 43% decrease in mortality and a 39% reduction in hospitalization against placebo. They reapplied for BiDil and in 2005 the FDA approved the first ever race-based drug. To this day if you go to BiDil’s prescribing page in a drug database it will include a specific race designation because it’s only approved for a specific race. Importantly too national organizations like the American College of Cardiology and American Heart Association endorse this race based recommendation for Black patients.
  • Now this is great that we have a recommendation for a group of people that is superior to the normal regiment but there are a few complicating factors to consider. Firstly the term ‘Black patient’ isn’t really scientific—how Black does a patient need to be in order to qualify for BiDil? What kind of Black as well: African, Latin American, Caribbean, etc? Likewise this means it has to be self-reportable but what about a light-skinned Black person that was adopted and didn’t know they had Black genes? It's all very…unscientific. Recently there has been push back against this explicit race-based recommendation since other effective drugs do exist (like the CCB and BB which were discovered in 2006, one year after BiDil). There was a new study in 2022 from UCSF that talked about the role of prescribing based on race but personally I think there are too many confounders (influencing factors) like socioeconomic status to accurately say BiDil should be done away with. BiDil was shown to be effective in the Black population but how it gets applied is another story.

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Liver Enzyme Distribution affects Metabolism—Once a drug is in the body it needs to be deactivated and removed eventually. This process of deactivating a drug happens during Metabolism which primarily happens in the liver via the Cytochrome P450 Enzymes. These CYP enzymes are like little factories that take up a drug and make slight modifications that remove its ability to affect the body. Each CYP enzyme is best suited for certain drugs while some enzymes, like CYP3A4 and CYP2D6, are able to handle a higher percentage of drugs. You can see in the pie chart above that some enzymes are more important in metabolism than others.

• That being said, the distribution of the CYP enzymes is not constant from one person to another. For example, in females they have a higher distribution of CYP3A4 than males which can be thought of them having more deactivation factories than males. This means if we were to give the same dose to a female and a male the female would metabolize the drug much faster and thus have a decreased effect. This is incredibly important because CYP3A4 accounts for 30% of all drugs including birth control, many psychiatric drugs, and chemotherapeutics meaning that females would need higher doses than males, in theory. The opposite is true for CYP2E1 which is higher in males than females and is a metabolizer of ethanol (minor) and caffeine (major) which means that higher doses of both would be needed to have the same effect male vs female. Neat eh? Like there are sex differences for CYP enzymes we are starting to discover racial differences in CYP enzymes: we have identified Polymorphisms or small genetic variability among the genes that encode the CYP enzymes. Truthfully this isn’t surprising, we know there is genetic variability in genes that affect hair or eye color, so it's not too surprising that the CYP enzymes are equally affected. What is interesting is that the racial differences in CYP enzymes can lead to wildly different enzyme activity levels that lead to clinically significant differences in drug response. Or in simpler terms, some races respond better to some drugs because they have different liver enzymes!

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• Let’s take a look at one drug, Amitriptyline (Elavil) used for depression and anxiety, and how Polymorphisms result in changes in response. Quickly let's take a look at the metabolism: we can see that Amitriptyline is metabolized by two enzymes, CYP2D6 and CYP2C19. If it is metabolized by 2D6 first then it converts into an inactive metabolite that is eventually removed from the body. However if it first goes through 2C19 then it is converted to an active metabolite, Nortriptyline which would extend the action of the drug than if it went through 2D6. But if it does go through 2C19 then it will be handled by 2D6 into an inactive metabolite (bottom right), so either way we need 2D6 to get rid of the drug.

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• So let’s look at what happens when we mess with the metabolism of Amitriptyline through 2D6. Well if someone is a 2D6 poor metabolizer then they would be unable to clear the drug quickly and so it would hang around in the body longer—so more anti-depression activity (and side effects). We find that up to 10% of Caucasians are poor 2D6 metabolizers meaning that they would have a better response to Amitriptyline than those who are normal metabolizers. Likewise we find that up to 51% of Asians are intermediate metabolizers which has led to an overall increased response of 74%! The flip side to this are the Ultrarapid metabolizers who would clear the drug extremely quickly through 2D6 thus leading to a decreased response to Amitriptyline. Up to 29% of Subsaharan Africans are found to be Ultrarapid metabolizers meaning that Amitriptyline (and other drugs going through 2D6) is the wrong option for them.

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• Looking at 2C19 we see a much different distribution among the races. Remember that 2C19 converts the drug into an active metabolite which would extend the activity of the drug—if you don’t go through 2C19 then you’d have a decreased response. So patients who are Oceanian have a whopping 89% chance to be an intermediate or worse metabolizer and so a much MUCH higher chance of decreased response to Amitriptyline. Compare this to Caucasian patients who have a 32% chance to have increased activity on 2C19 meaning a potential increased response to Amitriptyline.

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• Now is it really as simple as this? No, I am glossing over some of the finer details but I wanted to show how racial differences are a major factor in how drugs affect the body. Imagine if you had a population that had an 89% chance to have a decreased effect on birth control? Or what if you were a carrier of the HLA-B*5701 gene which means you are horribly allergic to the anti-HIV medication Abacavir (like up to 20% of Indians)? This is where the next generation of medicine comes from and the Clinical Pharmacogenetics Implementation Consortium is aiming to have their CPIC genomic guidelines become standard practice. In fact I am seeing more and more patients getting their liver enzymes done so we can see what kind of response they would have, especially if they have failed multiple drugs for a condition. Take a look at the guidelines page and see how many drugs are incorporated into the recommendations.

Regardless, pharmacogenetics has major impacts on how we treat patients every day but also may be a factor in some of the clinical disasters that we see. Afterall, 53% of Africans have decreased metabolism through CYP3A4 which is the major metabolizer of Fentanyl which may be a contributing factor why Blacks face higher overdose rates. If you haven’t, consider getting a pharmacogenomic test (many insurances will pay for it now) and unlock some secrets of your own body! Cheers!