All right, bioavailability, what is it? Let’s start with a definition. And so the definition of bioavailability is the fraction of the administered dose that reaches the systemic circulation. So, how much of that dose is getting into my systemic circulation? Well, what does the bioavailability depend on? First, it depends on the properties of the drug. Some drugs are very easily absorbed, other drugs are not easily absorbed. So the higher the absorption rate of the drug, the higher the bioavailability. So that’s what it means. The other thing that bioavailability depends on is the route of administration. Like we said before, if I give something intravenously, 100% of that drug is getting absorbed into the plasma. All of the mass that was in that needle is the mass that’s in the systemic circulation. But if I give a drug PO or by mouth, all of that drug is not getting into the systemic circulation and therefore, will have a decreased bioavailability. So what’s the equation for it? Well, the first equation is somewhat conceptual and this has us use those graphs that we kind of drew out when we were first talking about absorption. And so, what’s going on here is the bioavailability of a particular route of administration is equal to the area under the curve via that route of administration divided by the area under the curve had I given that drug IV. And so, when I say the area under the curve really if you remember before, we had time here and the plasma concentration here and so, let’s just use the example we had last time. I gave a drug IV, there was no distribution or elimination. I kind of had a graph that looks like this. This would be the area underneath the curve. Let’s say this is IV and this is our hypothetical situation. Whereas had I given that drug PO, the area under the curve would be decreased. So, what is area underneath the curve? AUC – so the area underneath the curve is proportional to the amount of drug absorbed. So let’s put this kind of all together. First off, bioavailability is a fraction. And so, because it’s a fraction, oftentimes you’ll see this written as F. So if I was going to say the bioavailability of a drug given PO. Let’s switch back to – let’s use blue. So, the bioavailability PO is equal to the AUC PO. So what is the AUC? We’ve already said it but it’s the if I gave a certain mass of drug by mouth, how much of that drug is getting into the systemic circulation? And I would divide that by the AUC IV. In other words, if I gave that same drug intravenously, how much of that drug would have gotten into my systemic circulation? So this is bioavailability. So this definition is a little conceptual. We’re going to make it a little more practical as we develop this concept. So what are some practical key points that allow us to really use this definition of bioavailability because I highly, highly doubt that you’ll ever be measuring an area underneath the curve of a graph unless you’re doing some sort of pharmacokinetic study. First off, let’s look at what area underneath the curve IV really means. So you can think of the area underneath the curve IV as the amount of drug in the plasma if 100% had been absorbed. In other words, this here is the total mass of the drug – the total mass of the drug administered. Think of this as the actual dose. I’m giving this much drug and if we assumed all of it had been absorbed, that’s actually the total mass that everything was there and then think of the area underneath the curve PO as the actual amount of drug that gets into the plasma. So, another way we could write this is the mass after absorption. whereas the AUC IV, you can think of this as before absorption. So if I was going to put this all together, I’m just going to reiterate this point because it is hugely important that AUC PO is the actual mass in plasma or is proportional to it and the AUC IV is the total mas given or the total mass administered. And so, which one is before absorption? Which one is after absorption? The mass in the plasma is obviously after absorption because absorption is the process for which a substance gets into the circulation. So this is after and this is before. All right, we’ve hammered this down. Let’s do a problem and make sure you get it. So here’s a problem. Metoprolol is a drug that works on the heart. The oral bioavailability is 50%. If the standard IV dose is 50mg, what should the oral dose be? Now I can almost guarantee you that you’re going to get some permutation of this question on a major exam. So you must know this concept so let’s work our way through it. Here’s a quick assumption just to help. Assume our goal is to reach the same plasma drug concentration in both cases. So let’s think about this the way a student might think about it. So, we’re going to go through 2 separate methods. One of them is going to be correct, the other one is going to be incorrect. So if I was a student and I saw this problem, I would first just jot down the things that I knew. I would say the bioavailability PO is 50% or 0.5. I’m not really sure what I should do with these yet so let’s continue. So I might take the equation for bioavailability and say all right, I know the bioavailability here is 0.5, the area underneath the curve for a particular route of administration divided by the AUC IV and I know something about IV here so, from my perspective I know what this is, I know what this is and I’m trying to solve for that. So I go through and solve for the AUC route and we know this route that I’m looking for is the oral dose, so that’s PO. And so, if I rearrange this equation, I get something like – if I just took this and brought it up there, I get the area underneath the curve by mouth or the amount of drug that gets absorbed into the plasma circulation if I took that drug by mouth is equal to the AUC IV x the bioavailability. So, I look at this. I know something IV is 50mg. So I write 50mg here. I multiply this by the bioavailability of 0.5. And so, if I do this, I would get an answer of 25 mg and hopefully, you can tell me that this is actually wrong. Now, the answer means something but it’s not what we were looking for. So what were we asking for? We’re trying to figure out what the oral dose should be. Is the oral dose that we’re looking for the dose before absorption or the dose after absorption or is it the amount of drug before absorption or the amount of drug after absorption. We’re trying to figure out the amount of drug we should give before absorption or the total mass of the drug that should be administered. So, really what I found here is not what the oral dose should be. Here, we unfortunately made the assumption that the oral dose was 50 mg and if it had a bioavailability of 0.5, how much would end up in my plasma? or what the actual plasma dose would be? And so, that’s what this 25 represents. And so, what I did is I wrote it down here in kind of a paragraph form. If I administered a dose with a total mass of 50 mg PO. After absorption, I would only actually have 25 mg in my plasma. That’s what this guy just solved. So remember, just to jump back to our last slide, the AUC PO right is the actual mass in plasma. This is after absorption vs. the AUC IV is the total mass administered – this is before absorption. So AUC PO, this is the actual mass in the plasma. This guy right here was our dose administered so to speak. That’s the total mass given. And we know this guy right here was just the bioavailability. So this is actually the useful equation that we should use. Before, I was saying kind of saying there was a conceptual way of using bioavailability with AUCs but really, there’s a practical way. And so now, let’s get to the practical method. And so, before we go any further, the approach here was wrong. Let me switch colors to red. It is wrong! So, which way is right? (singing) If loving you was wrong, I don’t want to be right… Okay, method 2. So, what I did here is I just took this equation that we kind of just figured out the practical equation so to speak for bioavailability and I kind of plugged it in here and that is the mass (the actual plasma mass), the amount after absorption is equal to the total mass administered (this is before absorption) multiplied by the bioavailability (F). And so, I need to go now back to my question with this you know new set of goggles and look at this question. So the oral bioavailability is 0.5. We’ve already established that. If the standard IV dose is 50mg, what should the oral dose be in order to get 50mg of that drug in my plasma because we want to reach the same plasma drug concentration. So, remember our first bread and butter equation. The most important concept. Concentration is equal to mass over volume. We’re assuming that volume is the same in both cases. We want our plasma mass to be the same. So in other words, I want here what I’m looking for. This is the actual plasma mass that I’m looking for. That is this guy. On the last part, we actually assumed it was the mass before absorption which was incorrect. And so, we’re looking for this oral dose and that’s here. So, in order to solve for this oral dose, I just need to divide both sides by bioavailability and this will give me the total amount of mass that I should administer or the oral dose. So, here are the mass (the total mass administered PO) is equal to the actual plasma mass and because I divided both sides by bioavailability, that’s kind of a tongue twister, I can solve here. So if this was our first core equation. I would say that this is our second core equation and this actually makes sense to me. Bioavailability is the fraction of administered dose that reaches the plasma. So, I take my total dose, multiply it by bioavailability and I get the actual amount that’s in the plasma. So here we’re trying to solve for what that dose should be and if I plug in my numbers, so the mass that I want in my plasma is 50 mg because I want an equivalent concentration divided by 0.5 and so I’m left with 100 mg, is the total mass I need to administer. In other words, a.k.a. the dose. So notice what happened. If I took this line of reasoning, I would’ve given them 1/4 the amount that I should’ve whereas if I thought of this the right way, I actually gave them the right amount. So let’s bring this back here and just do it one last time to make sure it makes sense. If I start with 100mg and I have a 50% bioavailability, I’ll end up having 50mg in the plasma and that would be the same as giving a standard IV dose of 50mg. Do you see how that works? And so this is actually a good rule of thumb. If something, Metoprolol’s bioavailability is around 50% and really for any drug that has an oral bioavailability of 50% if you know the standard IV dose then hey, I say oh I’m just going to double that and that’ll give me my oral dose. If the bioavailability was 25% right, I would just quadruple it and give them 400mg. I’m sorry I would quadruple it and give them 200mg, not 400. I hope this makes sense. Compare these two. You must know this for sure. This is our second core equation that we’re going to use to derive a bunch of our other equations. And so, there’s arguably 3 or 4 core equations in pharmacokinetics that you have to know. This is one, that’s two. Stop, think and repeat. So here are 4 questions that you should do on your own and once you have finished those, rejoin us when we jump into distribution in section 3. So I sincerely hope to see you there. Take care. Bye!