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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 14, 2013

Nasty Odor as a Drug Side Effect

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Posted by Derek

If you read the publications on the GSK compound (darapladib) that just failed in Phase III, you may notice something odd. These mention "odor" as a side effect in the clinical trial subjects. Say what?

If you look at the structure, there's a para-fluorobenzyl thioether in there, and I've heard that this is apparently not oxidized in vivo (a common fate for sulfides). That sends potentially smelly parent compound (and other metabolites?) into general circulation, where it can exit in urine and feces and even show up in things like sweat and breath. Off the top of my head, I can't think of another modern drug that has a severe odor liability. Anyone have examples?

Update: plenty of examples in the comments!

Comments (49) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Pharmacokinetics


COMMENTS

1. Adam B on November 14, 2013 11:49 AM writes...

How about cysteamine bitartrate, aka Cystagon,a treatment for cystinosis? Patients complain of a strong rotten-egg smell in sweat, breath and feces.

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2. Anonymous on November 14, 2013 12:03 PM writes...

Metformin has complaints of fish odour in the bottles depending on the source. Some have complained that it had transferred to body odour as well.

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3. interested reader on November 14, 2013 12:05 PM writes...

Carnitine, used for organic acidemias and some fatty acid oxidation defects at high doses can give patients a fishy odor. Phenylbutyrate, which we use for urea cycle disorders, can give people an unpleasant musty odor.

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4. Steve Calder on November 14, 2013 12:09 PM writes...

Fluoxetine Hydrochloride in Prozac causes only an increase in sweat, as far as I'm aware. This is quite interesting that the odor from the drug you mentioned is because of the sulfide breakdown process. I know that I wouldn't want to be caught smelling like rotten eggs! (Especially knowing that I'm definitely clean!)

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5. johnnyboy on November 14, 2013 12:12 PM writes...

Not exactly an approved drug, but administering DMSO (dimethyl sulfoxide) makes the subject exude a rather pungent, garlicky smell through the breath. Not a chemist so not sure which metabolite is responsible for the smell.

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6. newnickname on November 14, 2013 12:12 PM writes...

I knew someone who took garlic pills and they reeked from sulfur odors (breath, skin), presumably due to alliin --> allicin = allyl-S-S(O)-allyl and maybe further metabolism to volatiles.

Not a drug in the FDA sense, but drug-like.

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7. Hamilton M. on November 14, 2013 12:27 PM writes...

I've seen this reported as a side effect in variety of drugs containing thioethers or disulfide bonds, including some hallucinogenic phenethylamines, not just FDA approved pharmaceuticals. The antioxidant lipoic acid produces incredibly foul smelling urine, as does N-acetylcysteine. Sometimes it is unclear whether the odor is produced by the parent compound/metabolites or a downstream physiological change induced by the drug e.g., many binge users of psychostimulants like methamphetamine or mephedrone report foul body odor, but I feel this is likely from increased secretion of naturally occurring odorant compounds as opposed to a foul smelling methamphetamine metabolite.

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8. Anonymous on November 14, 2013 12:27 PM writes...

We know we're facing diminishing returns on R&D when drugs succeed or fail based on their smell.

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9. Anonymous on November 14, 2013 12:30 PM writes...

Fish oil?

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10. A Nonny Mouse on November 14, 2013 12:34 PM writes...

One of my compounds that went into first humans was converted into a capsesin like compound. The effects were only discovered when they went to the bathroom the next day. I'm told that the higher dose effects were none too pleasant on the rear!

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11. TEd on November 14, 2013 12:43 PM writes...

Along these lines, Dr. Shieberle presented some info at the Spring ACS regarding 'garlic breath.'

Sensomic analysis revealed that allyl methyl sulfide (CH2=CH-CH2-S-CH3) was the main 'offensive' odorant. Respiration volumes revealed a peak emission rate at 3 - 5h post-ingestion. AUC of the exhalate revealed that emission exceeded the contained mass in garlic, strongly implying bioconversion from other available garlic-derived sulfides.

Better living through chemistry. Skip the garlic bread or certainly the kimchee if you're hoping to get lucky after your 8:00 dinner date... Or work fast!

-t

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12. annon too on November 14, 2013 1:19 PM writes...

The odor situation with darapladib known even before it went into humans; the question would be the frequency of occurance and if the intensity was enough to stop people from taking it as a drug. Almost certainly, it is due to the thioether as pointed out by Derek, but the exact mechanism or reason was not yet elucidated despite much effort. One issue was the potential potency of thiol odors, and the great sensitivity of some human noses even compared to the high sensitivity of current analytical methods.

Much work was done to find alternative development candidates that did not carry the smelly problem. But, none compounds carried the same combination of desired qaulities eg activity and developability characteristics.

Those who finished the Phase 3 program would not have had enough of the odorous symptom to cause them drop out of the study.

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13. A Non Mousse on November 14, 2013 1:32 PM writes...

Methyl salicylate

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14. Gerry on November 14, 2013 1:54 PM writes...

As the first poster mentioned - cysteamine. Which is particularly horrible because it has to be given to small children who then smell bad. I had patients who had to be removed from school because the odor was so bad. Eventually, they chose progression of the disease rather than taking the drug because it disrupted their young lives so much.

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15. Dolph on November 14, 2013 2:02 PM writes...

Pilocarpine can cause a very strong, unpleasent body odor if used systemically for xerostomia. Somewhat resembling very concentrated urine.

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16. @kayakphilip on November 14, 2013 2:23 PM writes...

My wife actually worked on cystinosis and was involved in the development of an extended release version of Cystagon. The main issues with the non extended release of that drug were that a) the kids (and they all were kids or young adults, no-one lived long on that disease) all reeked, and the kids and parents sleep patterns were disrupted as the drug needed to be taken every 6 hours. Compliance was ok until the kids went off to college.

The extended release (and eye drops) seems to have positive effects on both issues.

An interesting story on how to get drugs available for very niche disease areas - only 2K people worldwide have this very rare disease.

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17. Anonymous on November 14, 2013 2:32 PM writes...

Well, asparagus makes my pee stink. But I really do love asparagus. According to Wikipedia, they're attributing that mostly to methane thiol and dimethyl sulfide which came out of a UK study published in 1987. I don't think they are right because they also say only about 25% of the population can smell that odor but everyone produces the metabolites and I don't know anyone who can't smell methane thiol or dimethyl sulfide. And I've used the former on a kilo scale (oh, joy) and generated the latter with all those Swerns I've done.

I also get beer farts. But I think that's from the formulation rather than the active drug substance in the beer. I also think that there must be a drug approved in France alone because I often get some unusual odors off French people.

More in line with the post, there's good old penicillin. Though it doesn't really qualify as a modern drug.

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18. Chrispy on November 14, 2013 2:41 PM writes...

How does one do a blinded clinical trial of drugs like this? It seems like it would be obvious if you got the drug vs. placebo.

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19. John Spevacek on November 14, 2013 2:53 PM writes...

Dang nab it #17 Anonymous, you beat me to the punch by 18 minutes!

Some 47 years ago, I was hospitalized with pneumonia and given lots of penicillin. I still remember the smell to this day of my urine and every once in a while, something smells close enough that I get a strong flashback that I'm 5 again.

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20. lt on November 14, 2013 5:22 PM writes...

Then there's http://swallowableparfum.com/ - a pill that is being designed to do nothing but make you smell (nice).

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21. Pennpenn on November 14, 2013 5:28 PM writes...

As far as I can tell, Darapladib failed because it didn't achieve it's primary endpoint, not because of it's smell. The odor was just a noteworthy side effect, which is apparently a noteworthy instance in and of itself.

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22. Cheese on November 14, 2013 5:28 PM writes...

Clindamycin is another one that makes you stinky. My friend's child was on it for MRSA and he smelled BAD!

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23. Pennpenn on November 14, 2013 5:32 PM writes...

Sorry, my comment (21) was meant for #8.

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24. Hurin on November 14, 2013 7:15 PM writes...

Probably just as well that it failed. I have a hard time believing that a drug that makes you smell like a thiol would end up with a good record in patient compliance. Personally I'd probably take my chances with heart disease.

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25. cheshire bitten on November 14, 2013 7:44 PM writes...

Not really what you are looking for, but the morning after my testosterone injection (I'm transgender) my whole room would stink of teenage boy, and it wasn't just a male smell, it was a very distinct smell I haven't smelt since high school, and its a smell I have never come across in adult cis* (non transgender) men.

*This is probably the last place I need to define cis as a concept, but as it isn't yet mainstream language I will.

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26. djm on November 14, 2013 10:11 PM writes...

Cyclosporine has a characteristic odour, somewhere between earthy and sickly floral. It's not particularly unpleasant though.

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27. samadamsthedog on November 14, 2013 10:17 PM writes...

Somehow we dogs know when certain diseases are about to become active. Like service dogs who know when their master is going to have an epileptic seizure. Since i'm not a service dog myself i'm not sure it's smell, but i'm guessing it must be.

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28. Lu on November 14, 2013 10:25 PM writes...

Lest Not Forget
The Joys of Asparagus

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29. navarro on November 15, 2013 8:19 AM writes...

in the long difficult road to controlling my runaway triglycerides i took baycol, cerivastatin, for about 6 months just prior to the manufacturer's voluntary withdrawl of the medication from the market. it gave me a pungent body odor, both sickly-sweet and fecal, that two showers a day and drakkar noir cologne barely kept in check. i had already told my doctor to find something else when bayer withdrew it.

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30. petros on November 15, 2013 8:23 AM writes...

Another drug with an unpleasant side effect is acarbose. When taken at the wrong intervals relative to food this leads to explosive, but generally odourless, flatulence.

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31. Nekekami on November 15, 2013 9:44 AM writes...

Some antibiotics I've taken made my urine and sweat stink like an industrial scale gasoline spill...

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32. rockhopper on November 15, 2013 9:50 AM writes...

Are there any therapeutic compounds that contain selenium or tellurium?
I think Te absorbed by the human body gets metabolized to dimethyltellurium which is excreted with sweat. Certainly not a nice smelling compound.

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33. Lucas on November 15, 2013 10:39 AM writes...

Modafinil (Provigil) makes pee smell utterly bizarre and thiol-y. Haven't noticed the smell in any other excretions, though.

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34. DannoH on November 15, 2013 12:42 PM writes...

Not a drug per se, but back in my younger and more stupid days I took a solid exposure to a particularly nasty diisopropylaminoethanethiol salt in solution.

Everything, breath, sweat, pee, etc smelled of a weird combination of garlic, skunk, dumpster juice, and lord knows what else. Showers and soap fixed it...for about an hour. Took about three days to clear my system. Is there no worse feeling that wondering "what is that god awful smell" and realizing that it is you?

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35. okemist on November 15, 2013 1:26 PM writes...

Profofol, di-isopropyl phenol gives a horrible flavor in the mouth upon injection.

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36. okemist on November 15, 2013 3:14 PM writes...

Profofol, di-isopropyl phenol gives a horrible flavor in the mouth upon injection.

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37. Anonymous on November 15, 2013 3:51 PM writes...

modafinil,
also coffee, dose dependent
milk products in sweat...

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38. dave w on November 15, 2013 5:36 PM writes...

#22: I've noted such an effect from clindamycin also: was taking it for a week a few years back to clear up an infection, and I definitely noticed it added an odd musty/earthy element to the usual scent of my sweat.

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39. Nobody on November 15, 2013 11:57 PM writes...

I once took preventative drugs for menengitis that turned my urine bright orange, but that's not quite the same.

However, I seem to recall that nitro would cause some rather horrid bad breath in patients. Hardly modern, but thought it deserved mention.

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40. MattF on November 16, 2013 3:13 PM writes...

I took a penicillin antibiotic some years ago and smelled like mold for a week. The doctor was amused.

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41. Anonymous on November 16, 2013 8:59 PM writes...

Selenium poisoning sometimes comes with a strong garlic smell on this breath

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42. Fletcher Christian on November 17, 2013 5:17 PM writes...

#11 TEd - Or make sure your dinner date eats garlic too! ;)

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43. Tristan on November 19, 2013 11:12 PM writes...

Not an odor problem, but I was once prescribed a proton pump inhibitor which I gave up on quick smart when the armpits of half a dozen of my t-shirts mysteriously had all their colour bleached out of them.

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44. Stu West on November 20, 2013 6:35 AM writes...

Absolutely the worst antibiotic for odour is ceftazidime. Smells (and can make sweat and urine smell) like cat pee.

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45. Eric Branchaud on November 20, 2013 10:25 AM writes...

Guaifenesin (Robitussin) gives a very distinct odor in the urine, which is unsurprising since it is renally cleared and tastes/smells horrible.

I've often pondered how bad it would be to chase a shot of Robitussin with a pot of coffee and a plate of asparagus. Maybe add some phenazopyridine for color while you're at it...

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46. Metaka Fraser on November 25, 2013 9:49 PM writes...

I seem to recall meperidine tablets inside the bottle smelling like burned rubber, though I don't know what they made the person who took them smell like. This actually led to an incident at work in which the pharmacist and I nearly took apart the conveyor belt because we were convinced it was burning up a belt somewhere, only for me to realize that no, it was not the conveyor, it was the bottle of meperidine I'd been counting out.

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47. William on November 27, 2013 8:54 AM writes...

All great examples but im sure it wasnt rejected because of that - more to do with outcomes. To back up @djm - Ciclosporin(e) (Neoral, etc) kept me a live [after a tx] so this isnt a complaint obviously - but had an unfortunate side effect that went beyond smell (though in liquid form it was like drinking oil and vile taste): it ruined my mother's shiny new car as it made my pores exude this terrible think oil type substance (!) and whenever I touched the paintwork the oil seemed impossible to remove! I now have tacrolimus (Prograf etc) and the problem went away within days. Certain drugs definitely change the way the body "breathes" so it comes as
surprise that it can make you smell etc. Certain drugs make urine smell definitely differently too.

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48. William on November 27, 2013 8:54 AM writes...

All great examples but im sure it wasnt rejected because of that - more to do with outcomes. To back up @djm - Ciclosporin(e) (Neoral, etc) kept me a live [after a tx] so this isnt a complaint obviously - but had an unfortunate side effect that went beyond smell (though in liquid form it was like drinking oil and vile taste): it ruined my mother's shiny new car as it made my pores exude this terrible think oil type substance (!) and whenever I touched the paintwork the oil seemed impossible to remove! I now have tacrolimus (Prograf etc) and the problem went away within days. Certain drugs definitely change the way the body "breathes" so it comes as
surprise that it can make you smell etc. Certain drugs make urine smell definitely differently too.

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49. Anon on April 1, 2014 11:46 AM writes...

Take a look at ezatiostat (Telintra). It is a glutathione analog prodrug GSTP1-1 Inhibitor.

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