77. Illuminating Elimination

The last Pharmacokinetics episode had finally been …Excreted!
 
 This episode  covers the ‘drug out’ bit of pharmacokinetics, including things such as:
 
 -What is clearance?
 -how to calculate half life
 and
 -doesn’t everything leave through the kidneys anyway? (That is sort of true, also shut up).
 
 Check out our prep notes (including for this episode) here. 

Transcript

Jame: 0:18

Callum, how are you doing?

Callum: 0:20

I'm good. I actually met someone really interesting the other day.

Jame: 0:24

Mm hmm.

Callum: 0:25

Yeah, he used to, used to reside in that island in the Mediterranean. Um, what's it called? The Greek one.

Jame: 0:37

Great.

Callum: 0:39

Oh yeah, yeah.

Jame: 0:39

my god. I had exactly the same pun, but go ahead. I won't interrupt you

Callum: 0:43

he's an ex Cretan.

Jame: 0:47

Fantastic.

Callum: 0:49

Um, and actually, he had a really interesting job as well.

Jame: 0:51

Mm hmm.

Callum: 0:52

He, he studied the

Jame: 0:54

a light salesman was he he was an eliminating excretion

Callum: 0:58

Ha ha ha ha. He, um, no actually, that must have been another excretion. No, this chap, he studied the production of a specific type of crockery. And really went very far into that. He was quite meta about it, you might say. And it was actually Bowles. He said he's quite meta bowl ism, meta bowl ism. So yeah,

Jame: 1:24

Wow. And that reminds me Callum What are we talking about today?

Callum: 1:28

Well, we're talking about, elimination, part three of our pharmacology jamisodes.

Jame: 1:35

So, specifically, elimination is the second half of, pharmacokinetics. So, where, how it gets in and where does it go is the absorption and distribution, part. And the metabolism and excretion is elimination. And we're going to talk about both of them, together. Because actually, quite a lot of antibiotics are just excreted unchanged. So, the metabolism episode would be, quite short. Let's see.

Callum: 1:57

Yeah, this is something I guess I hadn't really thought about that much before helping you a tiny bit of prep for context. Jane did a lot of prep on this and I helped for about 10 minutes maybe. And I guess, we often think about by availability. I think that's something I think about a lot when prescribing antibiotics and distribution is something that I definitely think about in the more complicated cases or where things aren't working. Metabolism, extrusion, not really thought about that much. We kind of think about it by proxy when we talk about patients with like a renal or liver failure. But, in a sort of abstract way, we're not really talking about the metabolism, extrusion mechanics. We're talking about, you know, what does the manufacturer say we should do for people with renal impairment? But yeah, just reading through what you've done. I think there's some really interesting points to come out in the discussion. So, Jane, where should we start with this?

Jame: 2:51

Well, uh, let's, uh, let's start with, metabolism, okay? So, like I said, not all antibiotics get metabolized, but what is the definition of it? It would be the chemical conversion of a drug into a form amenable to excretion. So, you will metabolize a drug to make it more soluble or more polar, so that you can then shove it out into urine, breathe it out, push it out. into the gut, from, your biliary tract. Those are the main three ways that you would get rid of a drug. Obviously through the urinary tract is the number one for most drugs. And there's two ways that you can do this. And they're called phase one and phase two reactions. Phase one are, redox, reactions or hydrolysis, and they will either ADD or unmask polar groups on the drugs. That would be hydroxyl groups, O groups or NH two groups. And then the second one is conjugation, which might be more familiar with, but these are adding various. polar groups of the drug. So if you added a glucuronate, you would call it glucuronidation. And if you add a glutathione, that would be called glutathione conjugation. There's a bunch. You can add sulfate, glycine, methyl groups, things like that. And they will make them more ionic and that makes them easier to, To get rid of, and this is really important for our lipophilic high volume of distribution drugs, because the drug will be constantly cycling between the, lipophilic tissues, which is where it wants to be, and sort of intermittently coming back into the plasma, and then it will be metabolized to a more, polar state, and that's what will get excreted out, otherwise the drug would stay in there, in the body for, days or weeks at a time. And like I say, the main places where this happens is the liver, kidney and the lung. The lung has a role to play in the metabolism. I think mostly just because there's lots of epithelium there and epithelia are involved with these reactions. So, what's phase one?

Callum: 5:04

So I guess, you know, you think phase one and then phase two, not all drugs go through phase one and then phase two. Some of them go directly to phase two. And as James said, some of them don't go for either phase one or two. They don't So phase one, this oxidization and reduction in hydrolysis process, that's usually happening with your cytochrome P four 50 enzymes. So that's something that I think everybody that works with drugs and or, you know, medical or pharmacists will be very familiar with.'cause we talk about that a lot in enzyme inducers and inhibitors. I think that's something that's in most people's lexicon. And what are those? So it is a large. family of hepatic enzymes that primarily are oxidizing drugs. So oxidization is loss of electrons and, mostly they're found on the hepatocyte endoplasmic reticulum. And they're responsible for most of the phase one metabolism and there's loads of different enzymes and essentially the way that you, you, they're all named, so they usually start with CYP, which stands for the cytochrome P four 50. And then the first number is the family, and then there's a letter, which is their subfamily, and then there's another number, which is the gene identifier. So you might get like Ccy, P three, A four, or CYP two. D6, etc. And the main ones, so resulting in 90 percent drug metabolism, are those ones, so 3A4, 2D6, and then several other ones. People will often talk about cytochrome, CYP3A4, and that's actually responsible for 50 percent of drugs. So, if you're going to remember any of them, remember that one, and that comes up time and time again. I definitely remember that from medical school.

Jame: 6:49

I think people are now concentrating on this more now that we can do, check for polymorphisms. So You may have heard about that, that kid that got, opiate toxicity and died through breast milk absorption of morphine, from his mother. was because she had a bunch of alleles for CYP2C. 9 or 19, I can't remember which, but anyway, that's one of the enzymes that metabolizes codeine to morphine. So she hyper metabolized,,the codeine into morphine, and she was actually getting drowsy and people were thinking that she was, you know, like stealing morphine and things like that, but that wasn't the case. He was just metabolizing the codeine ultra fast and then the kid was getting an extra dose. And so there's been this sort of drive in the clinical pharmacology world to, think about pharmacogenetics and not just, um, you know, the SIP isoenzymes, but now that we're able to do whole genome sequencing on humans for less than a thousand, dollars. if you send it to China and wait six weeks, you can get your entire genome sequenced. The cost of acquisition of getting this information is much lower. The question is what do you do with it once you've got the information? but I think a little bit of knowledge about CYP isoenzymes goes a long way actually. The one thing to point about the CYP enzymes is that they are generalist. Each isoenzyme. 3A4, 2D6, etc. will metabolize a bunch of different drug targets, and that means that they are slow at their job. As opposed to a very specialized enzyme that has one substrate, and, metabolizes it very quickly. Um, like, say, alcohol

Callum: 8:30

That's exactly what I was thinking about. I was like, I, I've got any example. I'm not sure this is right, but I was going to say, what about alcohol dehydrogenase? Cause I remember that from medical school and you can, yeah, saturate and stuff,

Jame: 8:41

Exactly. Yeah. but yeah, the SIP isoenzymes don't really work that way. They're a lot slower because they have to act on a lot of different substrates. So they're the, they are the prevent toxins from killing host enzymes. That's what their job is.. Let's talk about enzyme induction and inhibition, Callum.

Callum: 8:59

Yeah, so I think this is again something that people that are prescribing or using drugs will be familiar with and some probably key examples that you've got in your mind, which will come down to. So essentially, some medications you take can affect how the SIPs are expressed, and that's either through induction, so that might be increasing transcription, translation of the SIP isoenzymes, or slower degradation, or conversely, there can be inhibition, which is increased degradation of the SIP isoenzymes, and that can lead to increased or decreased metabolism of those substrates, respectively. And so, When we talk about inducers, there's a long list of drugs that we know to be enzyme inducers over 200. And this is usually a slow process. So induction can take, you know, one to two weeks. So it may not be so relevant when we're talking about antibiotics, which are generally given in shorter courses. Now, one example of an antibiotic. There is an exception, yes, of course. Um, there's always an exception. And, you're sitting at home thinking, the only enzyme and juicer I can remember is rifampicin, well, you're in luck, because that was the example. And, Rifampicin induction actually starts quite quickly, that's within 24 hours of taking it, and and it has 72 hours. So we talk about that a lot when we're prescribing people Rifampicin for infections because it has a lot of drug interactions, and that can be quite problematic for its use. There's loads of other ones, so, Jayme, you've got a, you've got a mnemonic here

Jame: 10:37

well, the pneumonia that I learned in medical school and I haven't learned a better one since then, is PC BRAS. So phenytoin, carbamazepine, barbidurates. Which are not very commonly used these days, although they're coming back into fast and intensive care. Rufampicin, alcohol, and sulfonylureas. So sulfonylureas are not sulfonamides, like sulfamethoxazole. Sulfonylureas are things like glycoside.

Callum: 11:03

Actually, now that you say PC Brass, I remember back to medical school, I didn't really like it, and I changed the mnemonic to being Crab's Pee.

Jame: 11:14

Is it the same thing?

Callum: 11:17

Well, Crab's Pee's got the same letters in it, so.

Jame: 11:20

Oh, okay, so a completely pointless change then.

Callum: 11:23

But I've remembered it better, until I didn't remember it because I'd forgotten it until right now,

Jame: 11:29

fine!

Callum: 11:30

Thanks, brain. So that's Inducers. So, what about inhibitors? So, obviously it's the opposite. So, they tend to increase the plasma level of substrate drugs, and that's because there's a decreased degradation by the SIPs. So, and this happens much more quickly than the inducers. So, it's over sort of one to three days. And again, we've got a Jame mnemonic.

Jame: 11:54

well, it's not mine. It's just the one that I think is

Callum: 11:57

A Jame approved mnemonic?

Jame: 11:59

Yeah, JAMA approved. So that's AO devices with devices is with two C's. So that's allopurinol, omeprazole, disulfiram, erythromycin and other macrolides, valproate, isoniazid, ciprofloxacin and other quinolones, cimetidine, Ethanol, acute ingestion and the sulfonamide. So that's the sulfamethoxazole component of Cotrimoxazole. So obviously there's three, antibiotic classes in there, isn't there? There's, the macrolides, the quinones and Corum, to think of as enzyme inhibitors. So

Callum: 12:34

Is it all microlites that do that or just some of them?

Jame: 12:37

I know it's, I think the effect is worse with erythromycin, but I think it's all of them in general.

Callum: 12:43

Just like erythromycin is the worst drug.

Jame: 12:45

Hmm. It is the worst drug, isn't it? Yeah. I wish I'm my worst enemy. Uh, and then important things that are missed by this mnemonic would be amiodarone, SSRIs, and grapefruit juice.

Callum: 12:58

Yeah, amiodarone is an important one to me. So if you've got a better mnemonic for either inducers or inhibitors, email in to idiaspodcasting at gmail. com and we will add it to the notes.

Jame: 13:09

I will not read that email. And that brings us Callum, to excretion. So, excretion has, the drug metabolism will result in three things. Either the drug is metabolized to an inactive metabolite, the drug is metabolized to an active metabolite, so for example, metronidazole, as metabolite is still active, Or, a prodrug has been metabolized to an active form, like codeine is metabolized to morphine. But, no matter what happened, the drug is now more ionic than it was, which means it will be easier to excrete it. And, like I said, the main sites of excretion are the kidney, the GI tract, the lung, so you can breathe it out, or the skin in sweat or tears, which is very, niche. We're only going to talk about, renal excretion, because that's the main one. And there are three stages to it. First is glomerular filtration. So about 20 percent of renal blood flow goes to the glomerulus, and then free drug metabolites will diffusively pass across the Bowman's capsule into, what will become urine. And about 80 percent of the renal blood flow serves the rest of the nephron, and some drug will be, polar drug, will be excreted into the urine through OAT and OCTs, which we covered previously. Finally, there's distal tubular reabsorption, so water will be reabsorbed along the tubule as you get towards the collecting duct. The concentration of the urine, drug, or metabolite, will increase, and then some molecules will diffuse back into the, tubule. Into the bloodstream down their concentration gradient, particularly lipophilic molecules, and then the rest of it will just get peed out. Any questions on that so far?

Callum: 15:01

no, I think it makes sense. And I guess we talked, we used the, we did the episode on, what antibiotics you could use for UTIs. And we talked a lot there about, how much higher the concentration of many antibiotics are in the urinary tract and how that's a big factor. beneficial thing for us when we're trying to treat infections in that area. And I guess this renal excretion really kind of explains why that is and why maybe some drugs aren't so useful because they might not be renal excreted.

Jame: 15:33

Yeah. Yeah. Yeah. Or, or very lipophilic, like the macrolides, for example. I don't know, that their excretion is particularly kidney ish. Yep. So yeah. So now we have to talk a little bit about. Calculations and things like that. So how do you measure, elimination? so you measure it with something called clearance. And that's defined as the overall rate of elimination of a drug from the body. So, metabolism and excretion. Almost all of it is hepatic or renal. And so, a term called total body clearances is those two in combination. And why do you care? Well, you're about to care because when we do our pharmacodynamics, when you see these, because we're gonna be talking about the therapeutic range for the antibiotic, which is basically, being above the MIC, of the. pathogen that you're trying to kill at the target site. And that is determined by the volume of distribution, which is the drug in, parameter and the clearance, which is drug out parameter. So how do you calculate it? It's defined as the amount of plasma that is completely cleared of the drug per unit time, assuming that you could clear the plasma in little clumps at a time. And you pertain that plasma concentration is the same as the entire body concentration. So it's similar to volume distribution. It's made up a little bit. And you express it as sort of mls per minute. So for example, aspirin is cleared at a rate of 650 mls per minute. So that's how much blood you could clear of the aspirin. over that unit of time. Do you get what I mean?

Callum: 17:28

Yes. Yeah. It's just I've looked at clearance before and be like, ah, yes, but never really thought like, what does it mean? And it's just getting your head around it. It's a bit, it's a bit confusing. So it is a sort of calculated measure. but we'll come on to why it's useful. I guess it's more useful for a comparison, isn't it? It's more about, how we use that data rather than, than how it's calculated being that important. But, yeah, it's good to understand.

Jame: 17:55

yeah, it's good to have a reasonable understanding of it. I don't think you need to learn how to calculate it and I don't think you really need to even keep this definition, in your mind for very long. But I, I think it's useful knowing about it because it helps you calculate half life. And drug half life, I think, is very useful because that does let me know, how long, the drug is going to, stay above the MIC from the, if I know the peak plasma concentration at time zero or time plus 15 minutes and the half life, I know roughly what's going to happen, to the drug. And the half life is defined as the time over which the drug plasma concentration will decrease by. by half, by 50%. And that, how do you calculate it, Callum? It is 0. 693 times the volume of distribution over the clearance. It's the volume of distribution divided by the clearance times 0. 693, gives you the half life. Now, what's 0. 693 doing there? It's the natural log of 2. Why is the natural log of two in there? There is a complicated explanation, but you don't need to know it. And I've forgotten it already,

Callum: 19:08

Okay.

Jame: 19:08

but trust me, it's very important.

Callum: 19:11

Okay.

Jame: 19:12

So yeah, just forget that it's there, but just know that the volume of distribution divided by clearance is in the half-life calculation. I'll give you examples. For example, and th this kinda lets you know, how often you need to give a drug to keep it above its MIC. So because. Of the way that half lifes work, 50 percent of the drug is removed at every time period. So if your peat plasma concentration is 4, then your, every half life you'll go from 4 to 2 to 1 to 0. 5 to 0. 25, blah, blah, blah. By about 5 or 6 half lifes, most of the drug will have been gone. So if your half life is like one hour, like a moxicillin's half life is one hour, you're going to need to give the drug quite frequently to keep on topping up the, the concentration in the plasma, and that's why we give it eight hourly. Whereas something that's got a long half life, say doxycycline, can be given once a day. Because, if it's 12 hours, you've only got two half lives before your next dosing interval. You see what I mean?

Callum: 20:11

Yeah, exactly. What about another drug, that you mentioned last episode that was called, Calum shut upacillin?

Jame: 20:18

Calum, shut up a cillin.

Callum: 20:20

Yeah, what's the half life on that?

Jame: 20:22

Um, the half life is none of your business.

Callum: 20:24

Oh, no.

Jame: 20:25

CalMuch, actually, that's how many hours it is. so,

Callum: 20:31

It's, interesting because I feel like half life is something that is in the lexicon of every prescriber and is something we talk about. but maybe we don't think enough about why is that, or maybe we don't need to know, I don't know. But, it is interesting to understand how, where that's come from, like how do we get half lives?

Jame: 20:50

yeah, well I think that knowing that it is dependent on the volume of distribution, which is the drug in bit, and the clearance, which is the drug out bit, in, you know, one divided by the other, that's important. Knowing that the natural login there doesn't give you any additional information?

Callum: 21:06

but then I guess the other thing to think about is that we know there's some things that can change the volume of distribution, which we talked about in DeLorean distribution, and there are things that can change clearance. So, uh, it's, you know, that will change the half life, won't it?

Jame: 21:22

Yeah, yeah, it will do, and this is where we're getting into the murky world of, dosing in, in, obese patients or dosing in intensive care, or people with sepsis who have hyperdynamic circulations, or kids and young adults who have very active kidneys so that you, your clearances is maybe not what you're expecting, unusually high. Okay. Like the classic would be, this person's on the top dose of vancomycin, but they keep on peeing at the bank. And so you can never get decent plasma levels and you have to switch to a different, drug. Well, why is that happening? Well, they have increased clearance relative to the, the average hospital population where you are able to get therapeutic levels, you know? So what take home messages from the, the first half of this. I think you need to know which antibiotics are enzyme, you know, inducers and which are inhibitors. So rifampicin is the inducer and macrolides, quinolones and sulfamethoxazole are the enzyme inhibitors. And then you have to think what effect that's going to have. The. The next thing is that what effect metabolism is going to have on your drug. Most of the time it will be inactivated., but sometimes the drug will have an active metabolite. So the example that I've got here is metronidazole. And so people have used that to justify twice daily dosing. of metronidazole, which some trusts, some hospitals have moved over to, and I think that is justifiable, particularly if you're going to be giving it long term for like, say, an amoebic liver abscess or something like that, you're reducing it from three times a day to twice a day means that you've essentially cut the dosage by a third and all those, Neurological manifestations of long term metronidazole use, they're dose dependent, and so you can prolong your potential administration of metronidazole by, by a third, by, by doing that. And also, if you're given it with cotrimoxazole and it's twice a day, it's easier for the patient to remember to take everything just in the morning and night, as opposed Or you also have to take metronidazole in the middle of the day. And lastly, there's something that we're going to cover in detail, soon I feel, Callum, which is, excretion modifiers. And the example I've got here is probenicid. so you, probably know, Callum, that down in Nadosh Royal Infirmary South, we have been using kefazolam with probenicid, which is a an anti gout treatment that doesn't have a license in the UK, but other countries do use it. It's kind of an old fashioned drug, and people stopped using it because it had lots of interactions. And what were those interactions? They prevented the excretion of, amongst other things, beta lactams. So if you want higher plasma levels of your beta lactam, then you can give the antibiotic with probenicid at the same time, and you will get, uh, more time over MIC. Uh, and so we've been using that with kefazolin, and we're about to start using it with flucloxacillin and kefalexin, or at least if I have my way, we will, Callum.

Callum: 24:31

I'm super interested in that because I think as we are in a, in a situation where we're increasingly trying to care of people at home rather than in hospital, and we use things like OAT and, you know, once daily IVs or highly viable available orals. You know, sometimes you don't have an option, like you want to use oxil and whatnot. I think that discussion around probit could be really impactful to, to sort of maximize our ability to, to ambulate patients away from the hospital.

Jame: 24:59

I agree. And I think the, we're, have to give props at this point to Richard Evertz, who's the, New Zealand clinician who's been pioneering the use of, of probenicides with beta latams in the community. But we will have to discuss it another time, Callum, because we have to, move on.

Callum: 25:16

Some really interesting takeaway points there. So, you said the first half. So, Jayme, what do you want to talk about now?

Jame: 25:25

So now, I've got a table, which I will have to release on, Twitter as well, with the metabolic data for, the antibiotics that we've been looking at., so far. So the first part of the table just has a bit of atoms and the second part has, other drug classes, the ones that are available in the UK, at least. And so I've got in columns. I've got the volume of distribution of the drug metabolism elimination route. And then the clearance, if I was able to get it, and then the half life, again, if I was able to, get it. So, for example, let's take penicillin. So the, penicillin G and V are, metabolized in varying proportions to penicillolic acid. That's the, penicillic moiety that people sometimes, are allergic, to. and then a small amount to six amino penicillinic acid and a couple of other active metabolites. And then mostly excreted in, in the kidney, that's sort of interesting to me because I've heard about the penicilloyl moiety, as a determinant of penicillin allergy, but I was somewhat surprised to find that when I went looking to see what other penicillins got metabolized to that, I couldn't find any information that any of the others were. And in fact, amoxicillin specifically has seven metabolites which are labeled M1 to M7, none of which appear to be penicilloic acid. so this kind of idea that they're a major part of penicillin allergy, I'm not sure it's true, actually, from what I could tell. And then, you know, when it comes to Amoxicillin, about, again, about most of it, it's renally excreted there. Is there anything else on the table that stands out to you, Cal?

Callum: 27:20

Is there anything interesting to me in this table? So much. A lot. I would really recommend looking at the show notes. Jayme has put a lot of work into this. And it was quite interesting to me how Sometimes you just, I always feel like, oh well, they must be known about all the drugs, but actually getting that data can be a bit tricky. The drug bank is a really useful resource, but yeah, I don't think that, I don't think this, this approach where, you've taken all the data and put it in one place is really available anywhere else. I think I've seen, I had a random Word document that some like, pharmacology professor had come and given a talk locally, like five years ago. Yeah, And it was really useful. And I, I look at that all the time because I'm like, when I'm talking about antibiotics and it's getting really complicated, I find this stuff really useful. But to be honest, it was annoying me a little bit because It wasn't like comprehensive, so there was always stuff that I was like, oh, and I didn't really have the tools to go away and do my own research because I was like, I didn't really know where that data had come from. So if you go into the bottom of the show notes for each one on notion, then James put his references. So actually that in itself is quite useful. And maybe you don't need to memorize any of this, but just know to go to drug bank or, the resources,

Jame: 28:38

But even then you don't need to tirelessly roll through Drug Bank because we've summarized it all here for you.

Callum: 28:44

It's not going to change, is it? It's, you know, the drug, what is known is known about the drugs.

Jame: 28:49

don't think so unless somebody actually does, goes back and does some proper PK analysis. Because a lot of this stuff is like historical, from the 60s and 70s and 80s. Most of the Benalactams are, have a half life of about, one to two hours, with a couple of exceptions. Keftraxone is about, say, six to eight, and ertopenem is four. And so that, that kind of long half life explains why those two can be given once a day. And everything else has to be given two or three times a day, on average. And, yeah, the other, I think in terms of metabolism, most of them are not particularly metabolized and are excreted into the urine, and that was a recurring, theme. And even the, if they are metabolized to an inactive metabolite, that usually comes out in the urine also. so I expect there to be a lot more variety in terms of where they left the body, but at least with beta lactams it seems that wasn't the case. Keftraxone is renally Metabolize excreted sort of 33 to 67% and hepatic excretion about, again, about 33 to 67% if you need What I mean? So if it's 67 of one, it's 33 of the other and vice versa. Yeah. So it's variable. And that sort of explains why you can occasionally get some hepatic or excretory side effects with, uh, with ceftriaxone, in particular

Callum: 30:17

Yeah, one thing that popped into my head and I, I don't know if there's data on this or not, but it made sense to me is that when we talk about C. difficile risk and we're going to talk in a couple episodes time about, the microbiome. Now, if you have a, I also thought about You have antibiotic. Antibiotic either goes in tablet or goes in vein. gets through gut, kills bacteria. Now, what I never really kind of appreciated, I guess, was like, if you take an oral antibiotic that's highly bioavailable, goes in quite quickly, and it's not really, in the gut that long, and then it might be come out the renal tract and excreted that direction. So maybe it doesn't have much interaction, but when you have drugs that are excreted hepatically, that's going to be a much more direct effect. So it then made me wonder, actually, if a drug is It's primarily excreted in, in bile, and in an active form, does that mean it's going to have a much higher risk for C.

Jame: 31:31

for c diff. Yeah. So that was, Suggested to me when it came down here, uh, by a consultant that I, trust, more than myself, certainly. And I, at the time, I hadn't really heard of that because I knew that keftraxone was excreted in the, in, in bile. And that's why in, in, you know, neonates, it was associated with jaundice and why they preferred keftotaxime because it isn't. And I. Knew that, say, comoxaclav was mostly renally excreted and there was very little, if any, Hepatic excretion. I don't know exactly how much there is, but I had never really heard this idea. And I had in my idea that in terms of C. diffs, they were, they were roughly the same. And I've since seen other reviews on C. diff risk, which are putting comoxaclav a slightly lower risk than, than, third generation Keflasporins. And so I don't know if that's part of that is because Keftraxone is hepatically excreted. Um, it's, Not something that I've seen across the third generation Keflasporin. So, for example, Keftazidime is about 85 percent excreted in the kidney at 24 hours, which means almost by definition that 15 percent is coming out somewhere else or in the kidney after 24 hours. So not a lot of that will be, even assuming that the remaining 50 percent is entirely pushed out into the, bile. That's still not as much as, say, you know, Keftraxone, would, and there's other ones like, say, Keftolazine, which is either third or fourth generation. Well, it's 100 percent really excreted. And so it's, being excreted in bile might play a little part in it, but it certainly doesn't explain it. It's the spectrum of the antibiotic that explains most of the C. diff risk.

Callum: 33:21

I guess it's like, you know, where it's excreted, but also, like, it's in your blood, so it goes to your gut, so there will be some,

Jame: 33:30

And, and the gut is vascular and, you know, like your, your gut will be exposed to the antibiotic.

Callum: 33:35

I just thought it was an interesting theory. I, I guess we don't have any Data to back that up, when you look at the table and you look at the things that are coming out, the things in my head that I'm like, those are the ones I would think about are the highest risk of C. diff based on the review articles that I've read and just, I guess what people have taught me, the things that stand out. quinolones people talk about a lot and that they do seem to have quite a high, percentage excretion that's not in the renal tract. Although interestingly, this is saying that levofloxacin. is much more really excreted than ciprofloxacin or moxifloxacin. Does that mean that levofloxacin potentially could be lower risk for C. diff? We can't claim that because we

Jame: 34:16

don't think so. I think, you know, once you get above, uh, the first gen into second generation quinolones, the C. diff risk is, uh, I think fairly constant. Um, uh, I've never seen any data suggest that Levo or Moxie have lower C. diff risk than Cipro.

Callum: 34:33

And the problem is, I think with C, everyone just wants an answer, which is like, what is the C

Jame: 34:38

I'm sorry, is this a C Diff episode and you forgot to tell me, Callum? Why are we talking about this all the time?

Callum: 34:43

uh,

Jame: 34:43

in your bonnet here, Sunshine.

Callum: 34:46

just think it's really interesting. I'm going to, I'll finish off on the C double seal, which is one other thing to say, which I guess is that we talk about it all the time and we, we categorize things into high risk or low risk and influences our decision making. But like getting reliable data on what is and is not a high risk CDA thing. And, we dichotomize it like that often and the review articles we have, like the data is so hard to know what the answer is, it's so complicated. but actually it's just unknowable. So anyway, sorry, jane, anything else you want to talk about for the table? I actually, I had one, one antibiotic I wanted to ask about, but I do wonder if it maybe needs an episode all of its own.

Jame: 35:28

Oh yes, do tell. Yeah,

Callum: 35:32

sitting in a meeting the other day and we were talking about double Vance. And we were going to give our double banking, however you want to say it, and we were talking about giving 1, 500 milligrams and then repeating that dose on the eighth day, and then not giving a very extended period of cover.

Jame: 35:48

that Yeah, 6 weeks, if I remember rightly.

Callum: 35:51

Yes, I think it's either four or six weeks, but, and then the question came up was Why is, why is that? Why, how does it give such a long cover? So I guess from what we've talked about, it's a very, very large molecule. So on distribution, we talked about having this very high molecular weight, and I think it's amphipathic.

Jame: 36:10

Yeah,

Callum: 36:11

And, uh, it's half life is 346 hours, which is, that's quite long, isn't it?

Jame: 36:21

yes, it is quite long Callum., yeah, so if you, so what's 346 divided by 24? That's 14 days. So you have a two week half life. And so the, I think the idea of giving it on, day eight is that you're halfway through that, that half life. I'm not sure pharmacokinetically it makes all that much sense, but that's certainly what was initially published. And then they measured the plasma levels over, I think, the next four or six weeks, I forget what. And basically the, you were always over the MIC, uh, of the, uh, of the pathogen. And as far as I know, this has only been, put in in sort of case reports and and I don't I'm not sure there's RCT evidence behind it, but it's it's cleared. So slowly. The clearance is 0. 9 mils per minute. It's very slow to get in. So, a week into to therapy, your plasma level has barely changed, really, It's, barely gone down and, this is what they were designed for, they were designed deliberately to be long acting and though I don't have data for, auto banking and, telebanking, but I'm sure they are similar in terms of their long half life. We played about with the glycopeptide structure until we found something that the kidneys didn't like to get rid of particularly fast.

Callum: 37:40

Here's another question. So we talked about dosing of drugs and that the half life and the clearance, behind that in the volume of distribution results in your dosing interval. So why is something like keftriaxone that has a half life reported of between 5. 8 to 8. 7 hours once a day and something like tigacycline, which has got a longer half life reported at 27 to 43? Dose twice a day.

Jame: 38:13

Because it's not just the half life that matters, it's the volume of distribution also. And if you look at the volume of distribution of tigacycline, it's sort of five to six hundred liters, whereas what's keftraxone's one. Keftraxone is 6 to 13 litres, so it's, these are two drugs, one of which is sticking very much to the plasma and the other one is, is, is leaving to go to the tissues, at a rate of knots and it's the interplay between the volume of distribution and the half life, which gives you your target MIC attainment, your AUC over MIC, but I don't think you can just look at the half life and think, Ooh, that's long. So I should be able to give it once every two days or something like that.

Callum: 39:00

Yeah. Yeah. Okay. That makes that makes sense. I am Because the volume of distribution is in the half life formula, but then you also have to look at it.

Jame: 39:08

Yeah, true.

Callum: 39:09

Yeah, you can't It's not one of those things we can just say like there's this one Number that will tell you everything about the antibiotic and you're done You can't just be like half life because actually the molecular weight and volume distribution are telling

Jame: 39:22

No, that's right, actually. That's right, actually, Cam, because if I think about what the half life for Tiggy would be, it would be 0. 693 times a really big number, the volume of distribution, divided by whatever the clearance was, and that gets you to, 27 to 43, which is the claimed half life that I've got on this table. So yeah, you're right, but it is an interplay between those things, which are leading to the sort of effectiveness of the, of the dosing.

Callum: 39:53

Yeah, so, I guess in this mini series, you know, for me, there's a lot of complexity and a lot of stuff that I wasn't aware of before, and I've not memorized all this stuff, but I guess how I'm going to use it is I'm going to come back in When I have these sort of questions to the notes and to the podcast episodes to refresh my memory to try and understand it. And when I'm teaching antibiotics to people, I probably will, most of the time when I'm teaching, I'll be quite junior people, so I'll probably stick to the episode we did about choosing antimicrobial at a very basic level. But what I'd quite like to do is, as we flesh out the sort of, Pharmacology aspects on here, we're doing PK, we'll do some PD and we'll do some other stuff. Maybe at the end, do a wrap up where we take a couple of antibiotics and conditions and then go through all the way from beginning to end. Because I think one of the problems is that when you get into the nitty gritty of any subject, It becomes really complicated and explaining it can be really hard because you're constantly cross referencing things and being like, there's some things in this episode that we're referring to that we've not talked about really that much yet, like the BD stuff. So hopefully you'll be able to stick with us through this mini series and, No, that's spiky, it's not bad. You, of course you'll stick through it, it's fascinating. And, at the end

Jame: 41:14

Well, I mean, there's no point telling us that now, Callum, because this is the last episode.

Callum: 41:18

Ha ha ha! Okay, well, yeah, if you're still here, great. And,

Jame: 41:23

uh, you,

Callum: 41:24

you, get a certificate in the post. So, James has taken us through there on part three. So we talked about, we blethered about bioavailability. We, Dillardon distribution. And now we're, illuminating elimination. And, we've talked a little bit about what elimination is. So it's metabolism and excretion. We talked briefly about metabolism, which is the chemical conversion of the drug form amenable to excretion. And that's got two phases. One is oxidation reduction or hydrolysis. And then the second part is conjugation. And we talked about the, uh, CYP enzyme systems and we talked about enzyme inducers Inhibitors talked about excretion, which is mostly renally and a little bit about half life and how that's calculated in clearance so hopefully you some of this will be useful and Reach out Jane will be tweeting out that table. So look out for that. Okay, right, well thanks again, James, for all the prep and hard work putting that together for us. I certainly learned a lot.

Jame: 42:31

Alright, Cal. Thanks for listening.

Callum: 42:35

Wow.