Pharmacokinetics | Drug Metabolism

all right guys now we're gonna 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 particular right of administration let's pretend oral gets absorbed across the gi tract then from there it gets into the portal system undergoes the first bass 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 going to get taken up by the liver the liver has special types of enzymes that's going to work on this drug metabolize it and once it does that it's going to do it a couple different things one is it can take a toxic substance and convert it into a non-toxic like 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 pro drug this is the only time where it

may actually activate a drug so you know pro drugs for example we've just recently covered antivirals valcyclovir so valcyclovir is the pro drug 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 pro drug will get broken down into the active drug so that's one type of thing so there's a couple different things that this metabo metabolic pathway of the liver can do with drugs it can take a toxic type of substance convert into a non-toxic type of substance second

thing is you can take a pro drug converted into an active drug but the most important one that we need to get rid of this drug is it takes an active drug and then converts this into a in active 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 pro drug 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 in activating 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 livers to take a 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 a drug may only have to go through phase one it may bypass phase one and under 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 pro drug converting into the active drug or we're taking a toxic component and turning into a non-toxic metabolite now in order to do that converting to the inactive drug we have to use special types of enzymes that we find inside of our parasites 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 the cells of this

liver called the apatocite in the epadocyte you 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 cyp 450 system so this is called your cyp450 system and this is a system of heme containing enzymes so what are these these are keem containing enzymes now what's important about these enzymes we have to talk a little bit about them all right so when we talk about the cyp 450 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 cyp 450 system there is two different like types of enzymes that i want you guys to remember that have 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 two is for the family of enzyme so this is the family of the 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 enzymes are the heme containing enzymes the two most important ones is the cytochrome 3a4 the family subfamily isozyme or cyp2d6 the family sub family isozyme these metabolize most

of our drugs okay 50 by the cyp384 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 easy 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 interverts 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's our cyp 450 enzyme it's going to have a little pocket where it has the ability to have things bind onto 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 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 soil because they can be easily reabsorbed i'll talk about it later well we want to convert it to 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 well 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 in its active form converting it

into an inactive form pro-drug to an active drug or toxic to a non-toxic metabolite by doing things like oxidation reduction or hydrolytic reactions making the 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 it can metabolize something super super slow and so because of that let's say that i have my cyp 450 enzyme here and i have a particular polymorphism within one of these cyp 450 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 metabolize 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 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 going to have to give them more drug to be able to reach the therapeutic effect because you're just chewing through the drugs so quickly that's an important concept so cyp2d6 where you have patients who are what's called rapid metabolizers 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 cyp 450 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 a 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 wanna 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 5450 system and alter the metabolism of other drugs that they may be taking let me

give 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 a what's called a cyp 450 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 cyp-450 inducers so these can act as cyp-450 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 cyp 450 inhibitor you can think about it as a slow metabolizer in a way now because 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 cyp 450 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 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

system when 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 what are some of the drugs that could potentially alter 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 they can even be more complicated than this you can actually have certain types of substrates interact with specific types of cyp-450 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 coip 450 inducer what does it do to the substrate that the actual cyp 450 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 cyp 450 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 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 they're 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 that you're gonna 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 p450 system is going to decrease and they can develop toxicity and the same thing exists actually with age you know when babies and little babies their enzyme system is not very developed in older individuals their enzymes are actually decreased so an 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 one little 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 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 opposite of everything we talked about here okay because we'd be trying to make active drug so think about that everything that we talked about with respect to the cyp cyp-450 inducers and inhibitors which was with respect to taking a 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 biotransformation now we gotta 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 oh thank goodness but they got all these annoying names so it's gonna 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 doesn't always have to only just

go phase one not phase two doesn't always have to just go phase two not phase one it can even go phase two two phase one so it can be all these types of process i think it's just important to know what's phase one what's the purpose of it what's some of the all you know things that can affect it and the same concept here is what's phase two what are the different enzymes that are 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 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 harder to excrete drugs that are you know non-polar 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 wanna do is in phase two we wanna make it even more polar we wanna make it even more water-soluble because by doing that i just make it a lot easier to

excrete this drug 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 sulfur groups which can give more polarity they can add on glutathione molecules okay glutathione son of a gun this thing's a beast's spell but glutathione molecules and then the last one which i think really one of the big ones is glucoronate 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 glutathione 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 glucuroni 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 acetyl transferase 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 last one which is my favorite the glucoronate molecule which you can have some

type of glucuronasal 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 feces or into the actual urine that's the whole process of the phase two 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've got to go to the next chapter of pharmacokinetics which is talking about excretion of the drug all right engineers let's do some practice problems we got question number six here it's on metabolism so we got a 68-year 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 pro drugs when it gets metabolized by the liver by the cyp450 system it gets converted from the pro drug which is the inactive form into the active form super important remember that she also takes ameprazol meprazol is a potent cyp450 inhibitor you can remember a part of that was the inhibitors where the key row right so the ketoconazole which is part of the azoll family erythromycin retonavir and ameprazole whereas the inducers were your rifampin your phenobarbital your phenetoin 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 pro drug into the active drug you won't have active clopidogrels 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 anti-platelet activity why because clopidogrel activity is reduced because of ameprazole inhibiting the cyp450 system you guys remember this diagram the drug gets taken out of the liver cyp 450 enzymes work

on the pro drug to convert it into the active drug if we give a very specific set of drugs you can remember again hero so ketoconazole the azoles are part of that group erythromycin retinovir and ameprasol these will inhibit this enzyme system will not convert the pro-drug into the active drug less of 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 a cyp 450 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 part of that whole process here's phase one which is active drug or pro-drug whichever one getting converted into the inactive it was pro-drug it'd be the active form and what we do in this process is that this enzyme does hydrolysis oxidation reduction and makes this more polar so it's easier to be excreted phase two you have transferase enzymes that add on the methyl group acetyl group sulfur group glutathione group or glucoronic 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 two so this would be your phase two and this would be a phase one which is the oxidation hydro hydrolysis and reduction reactions all right beautiful that covers metabolism in the next video for pharmacokinetics we'll talk about excretion going over all of those processes alright guys hope to see you there so [Music] you