Alright guys, so now we're going to talk about drug metabolism. So when we talk about the metabolism of the drug, we've already gotten to the point where we've given the drug via a particular route of administration, let's pretend oral, gets absorbed across the GI tract, then from there it gets into the portal system, undergoes the first pass metabolism, gets into the bloodstream, we've absorbed it. From there, it gets distributed through the circulatory system to different tissues. There's a lot of factors that we talked about with that.
now now what's really important is after the drug is gone and exert its effect it's time for it to say bye-bye and we have to excrete the drug from the body so in order for us to excrete these drugs sometimes we need to metabolize them so they're a little bit easier to be able to excrete into particular structures like excreting them into the urine, excreting them into the feces, exhaling them, we'll talk about all those different mechanisms, but it's important that we should be able to metabolize the drug, convert it from its active form into its inactive form. That's the most common thing. So when we take a drug, the drug has actually exerted its effect already, it's gonna get taken up by the liver, the liver has special types of enzymes that's gonna work on this drug, metabolize it, And once it does that, it's going to do a couple different things.
One is it can take a toxic substance and convert it into a non-toxic metabolite, if you will. That's easy to be able to be excreted. The other thing is it can take another type of drug, something like a prodrug.
This is the only time where it may actually activate a drug. So you know prodrugs, for example, we just recently covered antivirals. Valcyc. So valcyclovir is the prodrug to acyclovir.
So it'll get broken down into the active form of the drug. And so that's done by particular types of CYP450 systems. So the prodrug will get broken down into the active drug. So that's one type of thing.
So there's a couple different things that this metabolic pathway of the liver can do with drugs. It can take a toxic type of substance, convert it into a non-toxic type of substance. Second thing is it can take a prodrug, convert it into an active drug. But the most important one that we need to get rid of is the CYP450.
of this drug is it takes an active drug and then converts this into a inactive drug. And this inactive drug is now going to be a little bit easier to be able to excrete into the urine or excrete into the actual feces via the biliary system. So it's important to be able to remember that these are the three different ways that we're going to work via metabolism.
So one is we're either going to convert a toxic substance into a non-toxic. substance, activate a prodrug, or third thing, inactivate drugs so that they're easily able to be excreted from the body. Now, once we've done that, we need to focus our time a little bit more on this third part here, inactivating the drug. When we do this, we do it through two particular types of phases.
One is phase one, biotransformation, and phase two, biotransformation. This may seem like, okay, in order for the actual liver to take a drug, drug converted into an inactive drug, it has to go through phase one, then phase two. That must be how it works.
Most drugs, yes, but not all the time. Sometimes the drug may only have to go through phase one. It may bypass phase one and only undergo phase two. And sometimes it can do phase two and then phase one biotransformation.
So there's no perfect order to the way that the actual drugs go through this biotransformation phase one, phase two. It's just there's different enzymes and different types of things that we have to discuss that are important within these types of biotransformation. phases.
All right, so we understand drug metabolism. We're taking a drug, we're converting it into the inactive type of metabolite, or we're taking a prodrug, converting it into the active drug, or we're taking a toxic component and turning it into a non-toxic metabolite. Now, in order to do that, convert it into the inactive drug, we have to use special types of enzymes that we find inside of our hepatocytes.
So what I'm going to do is I'm going to take a little piece of this actual liver, and we're going to zoom in on one of the actual cells of this liver called the hepatocyte. In the hepatocyte, you have... have something called the smooth endoplasmic reticulum, or you have something called the mitochondria.
And in these, there's a special type of heme-containing enzymes. And these heme-containing enzymes are called your CYP450 system. So this is called your CYP450 system.
And this is a system of heme-containing enzymes. So what are these? These are heme-containing. Enzymes.
Now what's important about these enzymes, we have to talk a little bit about them. Alright, so when we talk about the CYP450 enzymes, there's actually some different types of families that we have to talk about that are very important. So when we talk about the CYP450 system... There is two different like types of enzymes that I want you guys to remember that had metabolized to be honest with you almost like 70 to 75% of most of our drugs. And this is CYP3A4.
I'll talk about what the three, the A, the four means. And the other one is CYP2D6. And again, I'll talk about what these mean.
But the cytochrome family is these heme-containing enzymes. The first number, so we have our heme-containing enzymes, right? Then we have CYP2.
The 2 is for the family of enzyme. So this is the family of the cytochrome P450 enzyme. Then you have the CYP2D. The D is for the subfamily. of that heme containing enzyme and then you have CYP2D6 and that is the isozyme of the cytochrome P450 system.
So it's important to be able to remember this okay so the cytochrome P450 enzyme are the heme-containing enzymes. The two most important ones is the cytochrome 3A4, the family subfamily isozyme, or CYP2D6, the family subfamily isozyme. These metabolize most of our drugs, okay?
50% by the CYP3 or 4, maybe like 20 to 25% for the CYP2D6. Now, what these guys do is they take a particular drug and they take an active drug and turn it into an inactive drug so it's easily to be excreted. And I'll explain how it makes it easy to be able to be excreted.
It takes a pro drug, converts it into the active drug, or it takes a toxic metabolite and converts it into a non-toxic metabolite. So here I'm going to zoom in. This is our CYP450 enzyme right here.
We're going to zoom in on it. So here is our CYP450 enzyme. it's going to have a little pocket where it has the ability to have things bind on to it but what it's going to do is it's going to take this particular drug and it's going to utilize specific types of reactions all right and the types of reactions that I want you guys to remember is it can do what's called oxidation reactions it can do what's called reduction reactions or it can do something called hydrolysis and the whole point of doing these types of of reactions is to take a drug that is nonpolar, right, and convert it into more of a polar substance. To take something that is more lipid soluble Because then it's easier to excrete things that are polar and water soluble than it is to excrete something that's non-polar and lipid soluble because they can be easily reabsorbed and I'll talk about it later. Well we want to convert into something that's polar and not just polar but also water soluble because it's easier to be able to excrete these types of things.
And so oftentimes what we'll do is is we'll do particular types of reactions where we'll take the drug and we'll add on an oxygen that has like a negative charge on it or we'll put like an OH group on it and so this allows for the drug to be a little bit more polar to have more opportunities to interact with water so being a little bit more water soluble and have charge on it so it's more polar and then it's easier to be able to be excreted so the cytochrome p450 system will perform this type of function of taking a drug and it's active form converting it into an inactive form prodrug to an active drug or toxic to a non toxin metabolite by doing things like oxidation reduction or hydrolytic reactions making the drug drug more polar and water soluble, so it's easier to be excreted. Now I think one of the big things to understand is not only does this actual drug, this enzyme system do this, but what are the things that can affect the ability of this enzyme to do its job? One of them is very, very interesting and it's kind of like an actual genetic concept.
So there's something called polymorphism. So genes can actually vary in the sense of how readily this enzyme can metabolize a drug. In other words, it can metabolize something so dang quick. or can metabolize something super, super slow. And so because of that, let's say that I have my CYP450 enzyme here, and I have a particular polymorphism within one of these CYP450 systems, particularly the most common where polymorphism exists is the CYP2D6.
That's actually the most common type where this one has a lot of polymorphism within it, right? And what I'm going to do is I'm going to have this enzyme chew through drugs super quickly. So it's going to be what's called a rapid metabolizer. It's a rapid metabolizer.
And if we think about most situations, rapid metabolizers, the primary thing that I wanted you to remember is they take an active drug, convert it into an inactive drug. Okay? So here is the active part of the drug, here is the inactive part of the drug.
If I chew through this, I'm quickly metabolizing this drug, I'm going to increase the concentration of my inactive metabolite. And I'm going to effectively decrease the concentration of my drug. Now, If I rapidly metabolize that'll decrease the concentration of the active drug and that may be problematic because we might not be able to accomplish the serum levels and so they may have a decreased therapeutic effect. We are gonna have to give them more drug to be able to reach the therapeutic effect because you're just chewing through the drug so quickly.
That's an important concept. So CYP2D6 where you have patients who are what's called rapid metabolized will chew through the active drug, decreasing the concentration of it, forming more inactive drug to be easily excreted, decreasing the therapeutic effect of that drug. The opposite situation here, let's say that you can have that CYP450 system, you have polymorphism.
So maybe it doesn't just act as a rapid metabolizer. Maybe it actually acts as a very slow. metabolizer. And so if it acts like a slow metabolizer, if I have a drug that is a very slow metabolizer, it's going to take a lot of time.
It's not going to be very good at being able to take the active drug and convert it into the inactive drug. So this process is going to be a lot slower. So I have a less inactive drug that's being formed and more active drug that's actually remaining inside of the blood.
Because of that, I will have high concentrations of the active drug. And in that situation, we'll have toxic side effects. So you'll start seeing the toxicity starting to increase in these situations.
So this is extremely important because there's actually been situations where maybe babies are very slow metabolizers of codeine. And if they slowly metabolize codeine, what happens is they actually can have high concentrations of the codeine within their blood causing the toxic side effects, like suppression of the respiratory system or excessive somnolence and sedation. So it's important to be able to remember these concepts when it comes to the phase one metabolism. You want to know why else phase one is so important?
There's a lot of people out there who have what's called polypharmacy. So they're taking many different medications at once. And because of that, because many drugs are metabolized via the liver, other drugs that they could be taking could be interacting with the CYP4 system, 450 system, and alter the metabolism of other drugs that they may be taking. Let me give you. you an example.
Let's say that a patient is taking, and I love this one because it's just the most scary one because it really kind of puts into perspective how important this is. Let's say that a patient is taking warfarin. Okay.
So warfarin is supposed to be able to thin out the blood, decrease clotting. If I give a patient what's called a CYP, they're taking another drug and the other drug that they take is what's called a CYP450 inducer, meaning it's going to increase the activity of the cytochrome P450 system. meaning it takes the active form of warfarin and converts it into the inactive form of warfarin. That's what we know, right? So this set of drugs that this patient could be taking will come and bind into this little pocket here.
When it binds into the pocket, it'll increase the activity of this actual enzyme and have it chew through the active drug. And so what will happen is effectively, as I'm going to increase the inactive concentration and decrease the therapeutic concentration of the active drug. So there'll be... less effect of warfarin now.
There'll be less warfarin that's needed to be able to produce the actual anti-clotting activity. So because of that, what does this do to the actual concentration of this drug? It decreases.
So now if you have a decreased concentration of warfarin, you're at higher risk of clotting. And there's many different drugs that can actually act as CYP450 inducers. So these can act as CYP450 inducers, meaning that they increase the activity of the CYP450 system, which increases the rate of metabolism. So they have increased inactive drug, decreased active drug.
If there's less of this active drug, there's a higher risk of clotting. So it's effectively thinking about this as though it's rapidly metabolizing the drug. If you have a CYP450 inhibitor, you can think about it as a slow metabolizer in a way now.
Because what happens is, So what happens is this drug, what it'll do is, is it'll actually bind to a particular pocket here on the actual enzyme. And what it'll do is it'll decrease the activity of this CYP450 enzyme. And let's say that we take again our example here of warfarin.
Here's the active form, here's the inactive form. If we give this particular drugs here that interact with the CYP450 system, decrease the activity of this enzyme, what's going to happen to the concentration of the inactive drug? Well, I'm going to decrease this pathway. So I'm not going to make as much of the inactive drug, I'm not going to form as much of the inactive drug, and I'm going to retain a lot of the active drug. If I retain a lot of this active drug, that means that the warfarin levels become...
super therapeutic potentially and they increase the risk of bleeding. So this is extremely important when you're giving particular drugs that are metabolized by the CYP450 system and you're taking it with other drugs those other drugs could affect its metabolism and provide toxic side effects or sub therapeutic effects. Very important. some of the drugs that could potentially alter and act like as an inhibitor. So these are some of them.
There's many many other. The list is absolutely insane and to be honest with it can even be more complicated than this. You can actually have certain types of substrates interact with specific types of CYP450 enzymes and they some of these may only act as inducers or inhibitors of a specific type of CYP450 enzyme. and they only will affect the actual particular substrate.
So it can get relatively complicated. I just wanted to make it very easy for you guys to understand what happens if you have a drug that you're taking with another drug, and that drug acts as a CYP450 inducer. What if you have a CYP450 inducer?
What does it do to the substrate that the actual CYP450 is metabolizing that drug? And then the inhibitors. If I take another drug, it works to decrease the activity of that enzyme.
What happens to the actual concentration of the therapeutic drug that I'm trying to metabolize or inactivate? That's all I want you guys to understand. All right.
So now we understand the factors affecting the phase one metabolism, which is primarily carried out by the CYP450 system. We know inhibitors. We know inducers. We know the polymorphism with respect to the CYP2D6, the rapid, and the slow metabolizers. Now what I need to do is talk about one other thing here that can affect it.
The liver is the primary spot of metabolism. A very small amount of metabolism can occur in the kidneys, a very tiny amount. amount of metabolism can occur in the lungs, a very minuscule amount can occur within the intestinal cells. It's primarily the liver. So if someone actually has diseases of their liver, their liver is failing, they have massive cirrhosis, acute liver failure, their liver all be jacked up.
Are they going to be able to have good cytochrome P450 enzymes, my friend? No. So their cytochrome P450 enzymes, the amount of them, the efficacy of them is going to decrease.
If the efficacy of these enzymes decrease, what happens to your ability to take the active drug? and turn it into the inactive drug. It's going to decrease.
And so because you're going to have less inactive drug, more active drug, more toxic side effects. And so it's important to remember that in patients who have liver disease, the efficacy of their cytochrome P P450 system is going to decrease and they can develop toxicity. And the same thing exists actually with age. You know, in babies and little babies, their enzyme system is not very developed. In older individuals, their enzymes are actually decreased.
So in elderly and in infants, their cytochrome P450 system is actually decreased. And so they can also develop toxic side effects because they have a decreased metabolism of the drug. In other words, less of it that's actually taking and converting the active form into the inactive form.
So one little cap. caveat. One little caveat because I know I got a little confused when I was reading it. What would happen though if we think about the inducers and inhibitors?
Same thing with the ultra rapid and slow metabolizers. If I had this cytochrome P450 system and one of the things that it was doing was this thing up here taking a pro drug converting it into an active drug. If that was the case then I'd be taking the inactive drug turning it into the active drug. So if this cytochrome P450 system was taking a pro drug converting it into an active drug it would be the exact same thing.
exact opposite of everything we talked about here, because we'd be trying to make active drug. So think about that. Everything that we talked about with respect to the CYP450 inducers and inhibitors was with respect to taking an active drug and inactivating it. If it was for turning a pro-drug into an active drug, you would completely flip the overall efficacy and process.
Okay? I hope that makes sense. All right, we talked about phase one by... biotransformation. Now we got to talk about phase two biotransformation.
All right. So for phase two biotransformation has nothing to do with the cytochrome P450 system, right? You're like, thank goodness. But they got all these annoying names.
So it's going to come back to be a little bit annoying, but I want you guys to understand what's the significance of phase two. And remember what I told you, a drug doesn't always have to go phase one, phase two. It doesn't always have to only just go phase one, not phase two.
It doesn't always have to just go phase two, not phase one. It can even go phase two to phase one. So it can be all these types of processes.
I think it's just important to know what's phase. phase one, what's the purpose of it, what's some of the things that can affect it, and same concept here is what's phase two, what are the different enzymes that are a part of this, what's the significance of it, that's it. So with phase two, let's kind of just pick up.
We had a drug here, we took the active drug in this situation here, and we converted it into the inactive drug. And how did we do that? Do you guys remember?
It was the cytochrome P450 system. We were taking and making this drug more polar, more water soluble, more charged so that it was able to be easily excreted because it's hard to excrete drugs that are you know nonpolar and lipid soluble because they can easily be reabsorbed. So by doing this I use that cytochrome P450 system to do the different types of oxidation reduction hydrolysis reactions and we talked about the inducers, inhibitors, liver disease, old, young and rapid slow metabolizers.
After the drug has gone through this process let's say that we do go through this per in a perfect world phase one and then we move into phase two with phase two what happens is we can take this drug that maybe is still not polar enough still not water soluble enough and what we want to do is in phase two we want to make it even more polar we want to make it even more water soluble because by doing that i just make it a lot easier to excrete this whether it be into the biliary system, which goes into the feces, or into the urine. So in order for me to do that, I need to use special enzymes. I don't want to saturate your mind with all of these enzymes because I think it's a little bit too much.
I just want you to know what's the purpose of this. So what can happen is there's a bunch of different transferase enzymes. Let's just keep it at that.
And these transferase enzymes can add on methyl groups. And these methyl groups may give a little bit more kind of a polarity to the drug. They can add on acetyl groups, which may give more polarity. They can add on sulfa groups which can give more polarity. They can add on glutathione molecules.
Okay, glutathione. Son of a gun, this thing's a beast of spell. But glutathione molecules. And then the last one, which I think really one of the big ones is glucuronate. Okay, we see this one a lot in physiology.
So we have a lot of these different types of molecules that can undergo what's called methylation, acetylation, sulfation, glutathionylation, and glucuronidation. And what happens is all these different types of transferase enzymes will take and add these things onto this inactive drug that's just a teensy bit polar. It's a little bit polar, a little bit water soluble, but not enough. We want to make it more water soluble, more polar.
So we add on this methyl group, acetyl group, sulfur group, glutathione group, glucuronate group. And what that does is it really gives more polarity to the drug, making it easier to be excreted. And so that's important. So for example, let's actually write out all these bad boys here. So we have this purple one.
This would be a methyl group, right? We said that one. So we would have like a methyl transferase. We would have an acetyl group. So you would have some type of acetyltransferase.
You would have a blue one, which would be the sulfur group that would give you some type of sulfur transferase. You have some type of glutathione transferase. So there is a glutathione molecule that you're adding on.
And again, these are super polar molecules. And then the last one, which is my favorite, the glucuronate molecule, which you can have some type of glucuronacyl transferase enzyme. And again, this is just going to add to the polarity of the drug.
So I think that's extremely important to be able to remember this concept, because now that I've actually made this drug a little bit more polar, think about how easy it's going to be to be able to excrete this into the biliary system and then into the feed. or into the actual urine. That's the whole process of the phase 2 biotransformation. So remember this process of where I'm adding these drugs on to the actual already slightly water-soluble already polar molecule it's a very important terminology that I want you guys to remember this is called conjugation reactions. So conjugation reactions will be taken care of by what's called your transferase enzymes in phase two, where the cytochrome P450 system will do hydrolysis, oxidation, reduction reactions in phase one.
Remember... Not every drug will go phase one, phase two. I could have a drug that can go straight into phase two metabolism and again, have just the conjugation reactions.
I can have drugs that only go through phase one and only go through oxidation reduction hydrolysis reactions. Or I can have drugs that go. through both of them.
So it's important to remember that. All right, my friends, now that we've gone through the actual metabolism, we got to go to the next chapter of pharmacokinetics, which is talking about excretion of the drug. All right, Ninjas, let's do some practice problems.
We got a question number six here. It's on metabolism. So we've got a 68 year old woman brought to the emergency department for treatment of an MI, myocardial infarction.
She's currently taking clopidogrel and aspirin, hopefully for that as an antithrombotic agent. Now really important to know here, clopidogrel is a prodrug. So when it gets metabolized by the liver, by the CYP450 system, it gets converted to a CYP450. worded from the prodrug, which is the inactive form, into the active form. Super important to remember that.
She also takes omeprazole. Omeprazole is a potent CYP450 inhibitor. You can remember a part of that was the inhibitors were the key row, right?
So the ketoconazole, which is part of the azole family, erythromycin, ritonavir, and omeprazole. Whereas the inducers were urofamp. your phenobarbital, your phenytoin, and carbamazepine. Okay?
So again, for the CYP450 inhibitors, they'll inhibit the CYP450 enzyme. That means that the enzyme will not convert clopidogrel from the prodrug into the active drug. You won't have active clopidogrel floating through the circulation. It won't be there to prevent thrombi from forming on a plaque. Therefore, the patient is at high risk for a MI.
So there should be, out of all of these, what would be the potential reason that they would develop an MI? reduced antiplatelet activity. Why? Because clopidogrel activity is reduced because of omeprazole inhibiting the CYP450 system. You guys remember this diagram?
Drug gets taken up to the liver. CYP450 enzymes work on the prodrug to convert it into the active drug. If we give a very specific set of drugs, you can remember again, Kero, so ketoconazole, the azoles are part of that group, erythromycin, ritonavir, and omeprazole, these will inhibit this enzyme system, will not convert the prodrug into the active drug, less of the active drug, and will not convert the the active drug to perform its function, which is preventing hopefully platelet plugs from forming on top of a plaque and causing a clot. All right, beautiful. Let's move on to the next question.
Which one of the following reactions represents a phase two reaction of that drug metabolism pathway? Remember phase one was CYP450 system. That was reduction, oxidation, hydrolysis.
So automatically we can get B, C, and D off the board because these are phase one reactions. If you remember phase two, it was acetylation. methylation, glucuronate additions, glutathione addition, and sulfation. Never in the world did I mention amination, which is adding an amine group on. So because of that, I would say that it's likely amination that does not involve this process.
Hydrolysis is not involved. Oxidation is not involved. Reduction is not involved. The only one that actually makes sense for phase two is sulfation.
And you can remember that because this was, again, a part of that whole process. Here's phase one, which is active drug or prodrug, whichever one. Getting converted into the inactive, if it was prodrug, it would be the active form. And what we do in this process is that this enzyme does hot hydrolysis, oxidation reduction, and makes this more polar.
So it's easier to be excreted. Phase 2, you have transferase enzymes that add on the methyl group, acetyl group, sulfa group, glutathione group, or glucuronate group to the actual drug and again make it even more water soluble, more polar, so it's easier to be able to excrete. So again, that's the important process for phase 2. So this would be your phase 2 and this would be your phase 1, which is the oxidation, hydrolysis, and reduction reactions.
Alright, beautiful. That covers metabolism. In the next video for pharmacokinetics, we'll talk about excretion going over all of those processes.
All right, guys, hope to see you there.