The Toxpod

No Drug is an Island

November 21, 2018 Season 1 Episode 1
The Toxpod
No Drug is an Island
Chapters
The Toxpod
No Drug is an Island
Nov 21, 2018 Season 1 Episode 1
Tim Scott & Peter Stockham
In the very first episode of The Toxpod, we talk about drug degradation.
Show Notes Transcript

In the very first episode of The Toxpod, we talk about drug degradation.

Where do the drugs go? What do they do when they get there? And how do we find them again? All good questions...

Contact us at thetoxpod@sa.gov.au



The Toxpod is a production of Forensic Science SA and the South Australian Attorney General's Department. The opinions expressed by the hosts are their own and do not necessarily reflect the views of their employer.

Tim:
0:11
Hello and welcome to the very first episode of The Toxpod. I'm Tim Scott.:
Peter:
0:17
I'm Peter Stockham.:
Tim:
0:17
And since this is our first episode, let me take a minute to tell you why we're making this podcast. Both Peter and I are passionate about the field of forensic toxicology and we love the conversations that go on between toxicologists and there are lots of ways that you can have these conversations: at conferences, through reading literature, publishing your own research, and this podcast is certainly not intended to replace any of those, but to add another medium into the mix where we can have the kind of conversations that toxicologists like to have. And for those working in our field who don't have a lot of access to literature and conferences and so on, this is a way that you can be part of the conversation too. So we hope you'll engage with us, we have an email address which we'll mention at the end of today's show. If you have a question or you want to hear more about a particular topic, let us know. So let's get into the first episode.:
Tim:
1:16
Today we're going to be talking about drug degradation. Drugs are like people, they're not static, they react to their environment, they can be changed by that environment, sometimes permanently. And so this episode we're going to be talking about the many points during their journey from initial dose to final detection where the drug can change into a completely new compound.:
Peter:
1:39
So why is this important? Well, in many cases you can't detect the compound that you're actually looking for, so you may not be able to tell your client whether the drug was there or whether the person was actually taking the drug they were supposed to be taking and that's when things like looking for degradation products become important.:
Tim:
1:54
So it's both qualitative and quantitative, isn't it? Because you might miss it in your screening or you might end up with the wrong level.:
Peter:
2:01
Yeah, that's right.:
Tim:
2:02
So one thing we're not going to be talking about very much in this episode is drug metabolism. Now obviously that is a change of a drug into another compound which happens in a living human being. But that's kind of outside the scope of what we're talking about here. Mostly we're going to be talking about chemical degradation, although we are going to be talking a bit about microbial degradation:
Peter:
2:23
Yeah and quite often those byproducts or the mechanisms of the degradation are completely different to what you might expect from human metabolism, but in reality drugs can degrade at many stages of a lifecycle of an analysis.:
Tim:
2:36
Yeah, even before consumption. So with pharmaceutical drugs, for instance, pharmaceutical companies do tests on the drugs before they release them where they, uh, put them into extreme conditions, basically things like pH, temperature, to see if they're going to degrade over time.:
Peter:
2:54
Yeah. So that's mainly to see how long the drug is useful for in storage.:
Tim:
2:58
And they can't account for all possible conditions obviously, but they put it through its paces pretty well, uh, and try and identify any degradation products sometimes too.:
Peter:
3:06
So this is really even before the drug gets into a biological matrix, isn't it?:
Tim:
3:10
But it may still affect what you're actually detecting at the end point.:
Peter:
3:14
So what are you talking about here? Do you mean...:
Tim:
3:17
Well, so like if a drug has degraded while it's still in formulation and then someone ingests it:
Peter:
3:23
Oh right:
Tim:
3:23
They're actually ingesting a different compound. And actually that's the same with changing of drugs during consumption. So you, someone might be consuming methamphetamine for example, they might be smoking it, but during pyrolysis it changes into a bunch of different things, we know that: dimethylamphetamine, phenylpropene, a whole bunch of different compounds.:
Peter:
3:42
Yeah but when that happens, usually the major component's still the main thing you're looking at there though, isn't it? So it's only a very tiny amount.:
Tim:
3:48
Yeah, it is usually. And as with the previous point with pharmaceutical drugs, the person is still actually consuming that degradation product, so it's not post consumption degradation, which is mainly what we're interested in and mainly what we're going to focus on.:
Peter:
4:03
Yeah so we're talking about how the drug disappears from the sample where it might've been at some time previously.:
Tim:
4:09
So if you're doing postmortem toxicology, one of the major areas of drug degradation which you need to take into account is microbial degradation after death.:
Peter:
4:19
So this could be termed in situ degradation of drugs, couldn't it, because it's still, the drugs are still in there in the body.:
Tim:
4:25
Yep and so you might get degradation of that drug over time. You might also get production of the drug over time.:
Peter:
4:32
So things like ethanol, for example is an obvious one.:
Tim:
4:35
Yeah that can go up or down.:
Peter:
4:38
Yep. I believe cyanide can also be produced by some bacteria and when you talk about glucuronide metabolites, that's obviously got a nice juicy sugar molecule in there that some bacteria will like to eat.:
Tim:
4:47
Yeah, so then you get the, you've got the glucuronide metabolite there, but then it actually gets converted by bacteria back into the original drug. So it can artificially elevate the levels that you're seeing.:
Peter:
4:58
It can give you a totally wrong answer. Well not a totally wrong answer, but an answer that wasn't necessarily the same as it was at perhaps the time of death.:
Tim:
5:05
Yeah. And it depends on the bacterial types, but obviously there's no predicting what bacteria is going to be present..:
Peter:
5:12
God knows what they get up to.:
Tim:
5:14
So a couple of drugs that are highly glucuronidated are paracetamol and morphine, so you might get those going back into their native form from the metabolite.:
Peter:
5:24
Yep, so that'll give you an elevated concentration of the free drug in your blood samples.:
Tim:
5:28
Yeah, so you might be saying something's a lethal or toxic level when it wasn't.:
Peter:
5:34
So some drugs are more susceptible than others to degradation, for example, risperidone and paliperidone, they can degrade quite rapidly in postmortem samples and that's been demonstrated to be through bacteria.:
Tim:
5:47
Yeah, but then other drugs have been put through their paces with bacteria as well, and they just don't seem to degrade much at all.:
Peter:
5:53
So it's entirely drug dependent. And so another example of a drug that can be produced, uh postmortem is GHB.:
Tim:
6:01
Yeah, that's notoriously hard to interpret the levels of GHB in a postmodern blood.:
Peter:
6:07
So when we're talking about the bacterial degradation of drugs, the bacteria we're talking about are the ones that are involved in decomposition of the body, and they of course come mainly from the gut because that's the main source of bacteria in the body. There's more bacterial cells in the body than there are human cells. Bacteria are mobile within blood, don't you think, Tim? They've got various ways of getting around, but it can largely be just through passive movement of the bacteria as they grow and expand out into the blood system.:
Tim:
6:37
And that all takes time after death for all that, all those processes to happen and the bacteria to spread, but one way that the speed of that can be increased is if there's trauma to the body, and the body's open to the environment, if you like, other bacteria can get in and you might get even in a body that's not seriously decomposed, you might still get something like ethanol being produced if the body's been exposed to outside bacteria, even for a short amount of time, especially if the temperature conditions are right.:
Peter:
7:08
Yep. That's also going to cause an increase in bacterial activity.:
Tim:
7:13
One way that people try to stop decomposition in bodies is by embalming and some countries do this a lot more than others and this involves putting, taking out the normal bodily fluids like blood and instead putting in formaldehyde and probably some other chemicals as well. It varies from region to region.:
Peter:
7:32
So not only are you replacing the blood that's already in there and so your results are going to be completely probably meaningless, I guess. You're also adding a very reactive agent formaldehyde into an environment where there's drugs which can react.:
Tim:
7:47
Yeah and people have reported uh methylation especially of drugs. Most drugs contain a nitrogen, uh, and so you can get methylation at the nitrogen, which can then convert it not only to a new compound, it can convert it into a different drug.:
Peter:
8:01
Yeah, like dimethylamphetamine can be produced or it may even get metabolites, normetabolites, returned back to their parent drug.:
Tim:
8:11
And it can even convert endogenous compounds, maybe putrefactive compounds into drugs. So...:
Peter:
8:18
Like uh, betaphenylethylamine is a classic one isn't.:
Tim:
8:20
It is. Converting it into a type of amphetamine depending on how it's, whether it's methylating it or ethylating it or whatever. So if you detect an NPS, a New Psychoactive Substance, in an embalmed body, it can be pretty difficult to know whether it's a result of the embalming or whether that is actually an NPS that was present or maybe it was an NPS that was present, but it's not actually the one that you're detecting because it's been changed by the embalming fluid.:
Peter:
8:47
So of course embalming's good for maintaining the integrity of the tissues and etc. But it's not terribly good for us toxicologists.:
Tim:
8:55
So moving on from the body itself to when the sample is actually taken. You take a blood sample, for instance, put it in a tube, you can still get microbial degradation because you're obviously taking bacteria as well even though you're putting it in with a preservative. So you put something like sodium fluoride into the tube and the idea is that it, it will inhibit bacterial activity.:
Peter:
9:17
So fluoride doesn't necessarily sterilize a sample of course, it just inhibits the growth of bacteria. I think it's through inhibition of its energy cycle.:
Tim:
9:27
But the problem with something like fluoride is that it's a chemical itself obviously, it can actually affect some drugs. So some organophosphorous pesticides, for example, are unstable in the presence of fluoride.:
Peter:
9:41
Right.:
Tim:
9:42
So it's always recommended that you get both preserved and unpreserved blood if possible, just in case you might need it for a certain type of testing. But the other big type of degradation you can get in a sample is chemical degradation.:
Peter:
9:57
So this is where the drug's unstable to just the natural circumstances in the blood, like water.:
Tim:
10:03
Yeah:
Peter:
10:03
Oxidation...:
Tim:
10:05
Could be that. Light, temperature, all of these different types of things.:
Peter:
10:09
So an example of that might be heroin and monoacetylmorphine perhaps. I think there are enzymes that also do the deesterification process but they're pretty labile to hydrolysis by themselves. Cocaine would be another one.:
Tim:
10:22
So storage conditions for samples are critical to have them in a dark frozen place with preservative.:
Peter:
10:29
So bodies, it can be pretty hard to control the conditions of a body, but once you've got a sample it's imperative that it's stored correctly and transported correctly as well.:
Tim:
10:37
But then the next step in the process is obviously when you take your sample out and now you want to start extracting your drugs out so that you can put them on some kind of instrument and start actually detecting them.:
Peter:
10:48
Yeah. So depending on what you're looking at, you may be exposing it to harsh chemicals, like bases and acids, which...:
Tim:
10:56
Yeah, you do that on purpose in order to extract them out. You're trying to optimize the conditions for extraction of that particular drug or maybe for a whole suite of drugs. But remember the drugs themselves are chemicals, they can react with their environment.:
Peter:
11:11
So like uh, zopiclone, and diltiazem.:
Tim:
11:14
Yeah zopiclone is unstable in alkaline conditions, for example. Uh diltiazem, same thing. Diltiazem actually is an interesting one because it degrades to its metabolite, desacetyldiltiazem.:
Peter:
11:27
Complicates things.:
Tim:
11:27
It does because you've probably already got some of the desacetyldiltiazem there, but you're increasing the ratio of that compared to the diltiazem.:
Peter:
11:36
Uh, so things like esters and amides, are often hydrolyzed during metabolism, but they're also a chemical degradation as well, aren't they?:
Tim:
11:43
Yeah.:
Peter:
11:44
So in the case of olanzapine, which is notoriously unstable for probably through a number of different routes, I don't think anyone's actually ever worked out how it, how or when it goes off in the process, but it's definitely been shown to go off in aqueous solution to form a hydroxy, uh, I think it's called hydroxy methyl olanzapine in one study.:
Tim:
12:02
Yeah, so that one's, olanzapine is a good example actually, isn't it, because it degrades under multiple conditions at multiple stages, bacterially, chemically.:
Peter:
12:12
So a lot of labs have uh, they use deuterated olanzapine to monitor this anti psychotic just so that they can tell whether there's any degradation happening during the analysis because it can vary from sample to sample. So in that, I think the workers showed that they could stabilize olanzapine to some degree in the blood samples, by adding ascorbic acid. But then of course you've got to think what's the ascorbic acid doing to other drugs you're looking for? So if it's a multianalyte assay, then you may be compromising other things. So you're talking about use of a reactive solvent, so even ethanol is quite reactive. That could do some trans-esterification.:
Tim:
12:47
That's right. That's right. You can get an ethyl group substituting for a methyl group...:
Peter:
12:52
I recall there was a batch of pentafluoropropionic anhydride, which was used for derivitization of morphine for GC analysis, GC/MS analysis, and it was tainted with a tiny amount of acetic anhydride. and the problem there was of course that there was a tiny amount of monoacetylmorphine being formed from the trace of...:
Tim:
13:13
Yeah, so that's something important to keep in mind as well, is that what you're putting into your test tube for extraction, you think you know what's in there, but there's gonna be some kind of impurities in the solvents, possibly in derivatizing reagents, in whatever you're using.:
Peter:
13:28
So of course that was picked up in the quality control steps, but nonetheless it shows there's a possibility that that sort of thing can happen.:
Tim:
13:35
And then when you get past the extraction bit, you're putting your extract onto your instrument, you can then get degradation on the instrument.:
Peter:
13:44
So you're talking about in a gas chromatograph or something?:
Tim:
13:47
Yeah, definitely if something's thermally labile, you might have problems on a GC/MS or any kind of gas chromatograph really. Uh, something like temazepam, or oxazepam are thermally labile, so you may see a small peak or you may not see anything. So with liquid chromatography you don't have the same thermal issues and with LC/UV you don't really have any particular issues except maybe the acidity of the buffer or something like that.:
Peter:
14:17
But the mass specs got a hotspot somewhere else though, hasn't it? So instead of getting thermal degradation at the beginning of the chromatography process, you may get it at the detector instead. So you might get some insource fragmentation or degradation.:
Tim:
14:32
So sometimes that fragmentation might be severe and you might not see any of the parent. Other times you might, you might still see mostly the parent, but the quantitation is going to be affected because...:
Peter:
14:44
Yeah, there's a whole range of different things that can happen in LC/MS that, because you've got the... as long as your fragmentation's consistent and you know it's happening, that's fine, but if the conditions in the source might change and you might have a larger amount of fragmentation even between samples, there may be some matrix effects at the source affecting fragmentation.:
Tim:
15:06
There is so much going on in LC/MS instruments that we can't see.:
Peter:
15:09
What about adducts Tim?:
Tim:
15:11
Adducts are another thing. You might get sodium ions forming instead of hydrogen ions.:
Peter:
15:16
Get a bad batch of water with lots of sodium in it and you can lose oxycodone sensitivity to quite a degree.:
Tim:
15:24
Yeah, so, and again that's part of the quality control process, is having check standards that you're running to make sure that you're not forming those things, you've got to be keeping an eye out for them.:
Peter:
15:34
I guess we're sort of digressing a bit from the main theme but it doesn't matter, it's all good fun. Okay. So I guess if we're talking about the extraction phase, I suppose one way to determine whether you're getting these sorts of problems happening is by looking at your calibrators. So if you get a little wonky looking curve, you can say, well, something odd is happening here.:
Tim:
15:53
Yeah. And there could be lots of reasons for it, but one of the reasons could be fragmentation in the ion source:
Peter:
16:00
And so some of these problems can be monitored by using regular check standards and things like that. Monitoring reference standards or sorry, your internal standards for a particular analysis over time to see how they change. That's a good way to catch up with these problems.:
Tim:
16:14
Yeah. If you've got a deuterated internal standard, for example, for zopiclone, which we were mentioning before is um labile in particular pHs then you can see if that's going off during your extraction. And uh, the problem comes of course, and this is a particular problem for zopiclone, where the deuterated internal standard might degrade into the same thing as the analyte, which just adds another layer of complexity to it.:
Peter:
16:39
So they didn't necessarily think about our particular analysis when they were making the deuterated standard.:
Tim:
16:45
Well, the problem is with making internal standards, usually they're making them in the cheapest way possible. So they're the easiest hydrogens to substitute, they're the ones where they're going to put the deuteriums.:
Peter:
16:58
So you put an ester or something thats got a deuterium in it, I guess.:
Tim:
17:01
Yeah, and that often happens. Unfortunately they're the first things that fall off if it's degrading. So speaking of standards, the other really important part of this whole discussion about degradation is reference standards and working solutions.:
Peter:
17:16
So how you're keeping them stable over time. Is that what you mean?:
Tim:
17:18
Yeah. Yeah, because they're... you might have a reference standard which you're keeping in your freezer and maybe it, so it's in the dark, it's in cold conditions, so the drug might not be degrading there, but you might be constantly getting that out, every day even, to do analysis with it. It's a real logistical issue.:
Peter:
17:37
So some labs deliberately if they have a working solution they're using all the time, they subdivide it into tiny aliquots, so that they only take out one aliquot at a time rather than the whole...:
Tim:
17:46
Like a single use aliquot?:
Peter:
17:49
Yeah, that's not a bad idea. And of course we were talking about solvents, the solvents during an extraction, for example, you can always have solvents during storage that can cause trans-esterification so storage in ethanol is not always a good idea.:
Tim:
17:59
For something like cocaine, for example.:
Peter:
18:00
Oh yeah, yep.:
Tim:
18:02
And then you get drugs which degrade in, sometimes very quickly in heat or light, so you take them out of the freezer, uh something like gliclazide degrades pretty quickly at room temperature. I'm not sure whether that's light or heat actually that's responsible for that degradation, but definitely in room temperature, in light, gliclazide degrades. Promethazine is another one, degrades very quickly.:
Peter:
18:27
That's cool that drug, how it goes so blue.:
Tim:
18:31
It is.:
Peter:
18:32
Is it blue or purple?:
Tim:
18:33
Yeah, I'm colorblind so I don't actually know, but it definitely changes color.:
Peter:
18:38
Yeah.:
Tim:
18:38
You can also get stereochemical conversion, so with zuclopenthixol, which is the Z form of clopenthixol, you can get that isomerizing into the E form. So some working solutions, you might need to prepare fresh every time, but if you've got a working solution which has a whole bunch of different drugs in it, for your systematic toxicological analysis or whatever, you might be doing some mega quantitation method, you just can't make it up every time, it's impractical.:
Peter:
19:11
No it's impossible.:
Tim:
19:12
So for some of those methods you might not be able to have a common drug in the method even though you see it all the time because it's just not stable in the working solution.:
Peter:
19:22
Or it may be that you just have it as a qualitative method rather than quantitative.:
Tim:
19:27
So if you've got a working solution that you're using regularly, you may want to monitor it each time you're using it to make sure that nothing is going off.:
Peter:
19:36
Is that why we have QC's?:
Tim:
19:38
And this is a problem, even though you've got QCs in your method, this is a problem if you've got a working solution and a QC solution, maybe a mixed solution of different drugs, and you might prepare them both at the same time and maybe they last for several months and yeah, they're staying consistent relative to each other, but are they just going off together at the same rate?:
Peter:
20:00
I hope not. No, no, that wouldn't happen.:
Tim:
20:03
No, I think that could happen! Which is why you've just got to be on the ball about these things and have processes in place to see if there's anything like that happening.:
Peter:
20:12
So we talked about all these problems they can have, which can be a bit scary, but how do you monitor for these?:
Tim:
20:19
Well, I mean one way is using full scan instrumentation. Even that's not foolproof.:
Peter:
20:25
That just means paying a lot of attention to peaks that you're not really interested in, doesn't it?:
Tim:
20:28
Yeah, it's very time consuming, but if you're using something like a triple quadrupole or if you're using a GC in SIM mode for example, you're just not going to see anything apart from what you looking for.:
Peter:
20:39
That's true, yep.:
Tim:
20:42
So I guess that's on one extreme...:
Peter:
20:46
Maybe that's better Tim? [laughing]:
Tim:
20:46
Ignorance is bliss, huh? Well if you're using LC/UV, it can be pretty easy to see if degradation is happening because you might see a reasonably large peak and a lot of the time it's going to have a similar UV spectrum because it might just be like one of those sort of functional groups which isn't really affecting the spectrum which falls off in the degradation. So the UV spectrum might even be identical, which makes it easy to see that it's come from that.:
Peter:
21:14
Yeah, so you might get lucky like that.:
Tim:
21:16
But if you're using mass spectrometry it is a little harder.:
Peter:
21:20
So in a full scan instrument where you've got a TIC, often there's hundreds of different peaks to look at. It's quite an arduous task to monitor degradation products.:
Tim:
21:29
Yeah, what do you look for? Which peaks do you look at?:
Peter:
21:31
You have got better things to do after all. [laughing]:
Tim:
21:34
You want to keep going with your work.:
Peter:
21:36
That's what I meant, yeah.:
Tim:
21:38
And it might not necessarily be a similar mass, you know. Sometimes it can be, there's some drugs which might degrade into, maybe dehydrogenation.:
Peter:
21:49
So it might only be a couple of mass units difference you mean?:
Tim:
21:52
Yeah, but who knows?:
Peter:
21:53
But if you're looking at one mass, you'd never notice that usually.:
Tim:
21:56
No, that's right. I guess maybe if you're only losing, you know, maybe one methyl group or something, the retention time might still be similar. So that's, maybe you only have to look around the peak of interest, but that's not always a guarantee either. Yeah, the time it takes to investigate unknown peaks which may or may not be degradation products, it just takes so much time to do that.:
Peter:
22:22
It's not possible to do that sort of degree of monitoring in routine analysis normally, is it?:
Tim:
22:27
No, I think often the way that these kind of degradation issues get picked up is when there's a problem. If, maybe you're not detecting your standard for some reason or your quality controls are failing or your curves are erratic. Something along those lines, there's got to really be something that triggers it because you're never going to be looking at every peak in a full scan analysis every time.:
Peter:
22:49
Yeah, that's just too much work.:
Tim:
22:51
But still this is where full scan instruments are really useful, when you do encounter a problem like that, you can actually go and have a look at the rest of the data. Otherwise the data just doesn't exist.:
Peter:
23:02
That's right, if you've got the... if you're using an instrument in SIM or MRM, for example, you wouldn't pick up any of these.:
Tim:
23:09
So one of the other difficulties is right at the end stage when you've detected what you've detected, maybe you have detected a drug, maybe you've detected some degradation products, they might be from microbial degradation, they might be from degradation during consumption. They might be some of them from degradation during the analysis, which you just couldn't eliminate. Obviously it's better to eliminate it if you can. Then what do you report at the end?:
Peter:
23:36
I would say if you're producing a compound during the analysis, like hydroxy olanzapine we talked about before, then that's probably a laboratory based problem that wouldn't be reported, but if it was, if it's a compound that's produced prior to receipt at the lab or even during storage, then it should be mentioned to some degree.:
Tim:
23:55
Yeah, sometimes reporting a bacterial degradation product for example, is not just important for the client to know for that compound, it also highlights that there has been bacterial activity and maybe that's affected the concentration of some other compounds as well, which you don't necessarily know the degradation products of, so you're not going to see that they've degraded necessarily.:
Peter:
24:17
You're talking about like risperidone, is that an example?:
Tim:
24:20
Yep:
Peter:
24:21
Hydroxybenzoyl risperidone, you might not be, if you're not monitoring for that, you won't even know the drug's degraded to some extent. So if you've got a, for example, a driver case where the sample may not have been stored appropriately and you find benzoylecgonine, but no cocaine. There's an issue there of course, if, was there cocaine in the person's system at the time of driving or not? Or was it just an old dose?:
Tim:
24:42
Yeah, so difficult where they, where the degradation product is also a metabolite. So with the nitrobenzodiazepines for example, like flunitrazepam, one of the metabolites is seven amino flunitrazepam, but it's also a bacterial degradation product.:
Peter:
24:58
Yeah, so they're hard to report, especially in post mortem cases where they're going to be very rapidly chewed up by bacteria.:
Tim:
25:04
Yeah. And hard to interpret because you're normally going to find uh, even if it's a sort of a recent dose, you're going to find flunitrazepam and seven aminoflunitrazepam even before any degradation because it's there as a metabolite, but if you want to use the ratio of the metabolite to parent to try and work at how long since the dose or that kind of thing, which can be tricky anyway, it's made even more difficult by the fact that some it's degraded.:
Peter:
25:30
That's right. You can never really get a true answer.:
Tim:
25:32
So what are your thoughts about quantifying the degradation products? Do you think there's ever a point to quantifying them?:
Peter:
25:39
I think there is. When you're talking about the seven aminos, for example, it's pretty important.:
Tim:
25:43
What if there's been complete conversion of the parent to a degradation product, or as far as you can tell, maybe you can never completely tell, but, because maybe it's degraded to other things as well, but if there's been complete conversion, let's say of risperidone, to hydroxybenzoylrisperidone...:
Peter:
26:02
That could be equated back to an approximate concentration of risperidone, but always with a disclaimer that you can't ever really be certain that that's where all the risperidone has gone, it might have gone to a number of different products and you only happened to be looking at one of them.:
Tim:
26:16
Yeah.:
Peter:
26:16
So it is important to quantify them I think. If you can get the right standards.:
Tim:
26:21
That's the rub, isn't it? Because a lot of these things, standards aren't really available. A lot of people might synthesize them themselves when they're doing the research to try and find out what they are. That doesn't mean they're commercially available.:
Peter:
26:35
Sometimes they're available through the pharmaceutical company if they happen to be a minor metabolite and sometimes if you find a new degradation production and you contact the pharmaceutical company who originally did the research, sometimes they do have large stocks of these metabolites that they can give out occasionally.:
Tim:
26:52
Or maybe even if it's something they found during their forced degradation studies, as we were mentIoning earlier, they may have some leftover.:
Peter:
27:00
Yep, but that's not really a sustainable source I think. If it becomes a popular enough degradation product for the tox community, then they should eventually be manufactured and sold as certified materials.:
Tim:
27:12
I guess one of the main practical outcomes of all of this, these issues around degradation, is that it's almost impossible to have one method which covers every drug because some drugs degrade in this condition or that condition...:
Peter:
27:28
They mighteven degrade in the extract that you're using, like olanzapine, for example, degrades in aqueous extracts.:
Tim:
27:34
And so, as tempting as it is just to have one method for everything, you really have, you're really making some compromises if you do that.:
Peter:
27:41
Never that simple.:
Tim:
27:43
Well, that's it for the first episode of The Toxpod.:
Peter:
27:46
I hope you have enjoyed our ramblings about various toxicological problems and how to make your life more difficult.:
Tim:
27:51
If you want to get in touch with us, you can send us an email at thetoxpod@sa.gov.au. Thanks for listening and we'll see you next time.:
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