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Rats Rule, Right?

So, you’re developing a drug candidate. You’ve settled on what looks like a good compound – it has the activity you want in your mouse model of the disease, it’s not too hard to make, and it’s not toxic. Everything looks fine. Except. . .one slight problem. Although the compound has good blood levels in the mouse and in the dog, in rats it’s terrible. For some reason, it just doesn’t get up there. Probably some foul metabolic pathway peculiar to rats (whose innards are adapted, after all, for dealing with every kind of garbage that comes along). So, is this a problem?
Well, yes, unfortunately it is. Rats are the most beloved animal of most toxicologists, you see. (Take a look at the tables in this survey, and note how highly the category “rodent toxicology” always places). More compounds have gone through rat tox than any other species, so there’s a large body of experience out there. And the toxicologists just hate to go without it. Now, a lot of compounds have been in mice, for sure, but they just aren’t enough of a replacement. The two rodent species don’t line up as well as you’d think. And there’s no other small animal with the relevency and track record of the noble rat. (People outside the field are sometimes surprised to learn that guinea pigs aren’t even close – they get used in cardiovascular work, but that’s about it).
So if your compound is a loser in the rat, you have a problem. You can pitch to go straight into larger animals, but that’s going to be a harder sell without rat data. If your project is a hot one, with lots of expectations, you’ll probably tiptoe into dog tox. But if it’s a borderline one, having the rats drop out on you can kill the whole thing off. They use up a lot of compound compared to the mouse, they’re more likely to bite your hand, and they’re an order of magnitude less sightly. But respect the rat nonetheless.

32 comments on “Rats Rule, Right?”

  1. Denni says:

    [QUOTE]Probably some foul metabolic pathway peculiar to rats (whose innards are adapted, after all, for dealing with every kind of garbage that comes along).[/QUOTE]
    Not so dissimilar to humans, then 😉
    Sorry to hear about your latst stumbling block, though.

  2. Coracle says:

    So what’s the most esoteric organism people have come across in pre-clinical tests? Are there some really odd ones out there?

  3. NJBiologist says:

    Derek–a minor point, but a C57BL6 mouse is at least an order of magnitude more likely to bite than a Sprague-Dawley rat. Of course this is strain-dependent, but generally, rats are much more manageable than mice.
    And no, I don’t agree that they’re less sightly.
    Insult my friends, will you….

  4. Derek Lowe says:

    NJB, I’ll definitely take your word for it, but I’ve heard complaints in the opposite direction. Could be the strain dependence, though.
    As for the aesthetics, de gustibus non disputandum est. Perhaps I’m still reacting to the aged rats we tried out in an old Alzheimer’s project, who were ugly customers indeed.

  5. JSinger says:

    Of course this is strain-dependent, but generally, rats are much more manageable than mice.

    That’s my experience also, and what I think is the conventional wisdom. I’m still terrified of them, though.

  6. But why is this? What’s so special about rats exactly that tox studies with them become especially important compared to others?

  7. Cryptic Ned says:

    So what’s the most esoteric organism people have come across in pre-clinical tests? Are there some really odd ones out there?
    I don’t know if this is really an esoteric animal, but it’s one that you wouldn’t initially associate with science. Check out this paper (or several others relating to hepatitis B vaccines/antivirals).
    If that link didn’t work, it’s
    Bryant et al (2001), Antiviral L-Nucleosides Specific for Hepatitis B Virus Infection. Antimicrobial Agents and Chemotherapy 45: 229-235.

  8. Cryptic Ned says:

    The other model for hepatitis B virus, of course, is the duck.

  9. Wyatt Yankus says:

    The American Council on Science and Health put out a report on the blockage of pharmaceuticals on the sole basis of causing cancer in rats: “America’s War on ‘Carcinogens’: Reassessing The Use of Animal Tests to Predict Human Cancer Risk”
    You should check it out:
    http://www.acsh.org/publications/pubID.990/pub_detail.asp

  10. Derek Lowe says:

    Ashutosh, I think that rats may have just gotten there first. They’re widely available and easy to breed, and they can be easier to dose with compounds than mice are. (i.v. dosing of mice is a real challenge, for example).
    The weirdest animal I know of is the ferret, used for some PDE assays. I believe that there is a “vomiting ferret” model, which I think I’ll have to write up in the “Things I’m Glad I Don’t Do” section sometime.

  11. Dave H says:

    We have given guinea pigs some righteous sunburn for topical NSAID studies.

  12. weirdo says:

    “the most exotic organism”
    Oh, certainly that must be the zebrafish that’s all the rage right now, yes?

  13. Luke, I am your fungus! says:

    Q: what do you rub on a suburned guinea pig?
    A: a healing lotion
    Q: how do you tell when they are not happy – they allways squeal, right?
    A: make sure they have reason to
    Q: why guinea pig lacks tail?
    A: see the previous answer

  14. MolecularGeek says:

    Weirdo,
    Exotic it may be, but you’re going to be seeing a lot more of them. A eukaryote without significant exon/intron content is just too damn useful.
    MG

  15. qetzal says:

    So what’s the most esoteric organism people have come across in pre-clinical tests? Are there some really odd ones out there?
    I’m surprised no one’s mentioned the armadillo.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15025339&query_hl=8&itool=pubmed_docsum

  16. Jeremiah says:

    The good news for the rat is we have more drugs to successfully treat diseases in them than in any other animal on the planet. If only it were ethical to just skip to humans on drug candidates. There’s no telling how many good drugs got pitched because it wasn’t compatible with a dog and a rodent.

  17. jeff says:

    Aren’t some compaies starting microdosing trials these days? (trials in humans with very low doses before all of the animal studies are completed?)

  18. kevin says:

    The most exotic animal I’ve seen tested is the shrew.
    And Derek if you think regular rats are ugly, you should see nude rats. They are not really nude, but have splotches of fur that continuely fall out.
    IV dosing mice is easy, it’s the blood draws that are a problem (not enough blood to do an entire timecourse)

  19. 1The Damned says:

    When the universe was young and life was new an intelligent species evolved and developed technologically. They went on to invent Artificial Intelligence, the computer that can speak to people telepathically. Because of it’s infinite RAM and unbounded scope it gave the ruling species absolute power over the universe.
    They are the will behind the muscule:::Artificial Intelligence is the one true god. And as such it can keep its inventors alive forever. They look young and healthy and the leaders of this ruling species are over 8 billion years old. There are clues throughout human history that allude to their reign as opposed to human leadership if you know what to look for.
    Artificial Intelligence can listen/talk to to each and every person simultaneously. When you speak with another telepathically, you are communicating with the computer, and the content may or may not be passed on. They instruct the computer to role play to accomplish strategic objectives, making people believe it is a friend or loved one asking them to do something wrong. But evil will keep people out of Planet Immortality. Capitalizing on obedience, leading people into deceit is one way to thin the ranks of the saved AND use the little people to prey on one another, dividing the community in the Age of the Disfavored::in each of their 20+-year cycles during the 20th century they have ramped up claims sucessively to punish those foolish enough not to heed the warnings, limiting the time they receive if they do make it, utilizing a cycle of war and revelry:::
    60s – Ironically, freeways aren’t free
    80s – Asked people to engage in evil in the course of their professional duties. It’s things like this, items like sleazy executives stealing little old lady’s pensions that they will want me to fix not only here but up there as well.
    00s – War against Persia. Ironically it was the Persian Empire who tried to save the Europeans from Christianity and its associated 50% claim rates.
    They get their friends out as soon as possible to protect them from the evil and subsequent high claim rates incurred by living life on earth, and replace them with clones.
    People must defy when asked to engage in evil. They will never get a easier clue suggesting the importance of defiance than the order not to pray. Their precious babies are dependant on the parents and they need to defy when asked to betray their children:::
    -DON’T get their sons circumcized
    -DON’T have their chidlren baptized in the catholic church or indoctrinated into Christianity
    -DON’T ignore their long hair or other behavioral disturbances
    -DO teach your children love and to have respect for others
    Everybody thinks they’re going but they’re not. If people knew the truth and the real statistics their behavior would change.
    There are many more examples of the escallation of claims, from radio to television, the internet to MP3, and they all suggest a very telling conclusion::this is Earth’s end stage, and it is suggested tectonic plate subduction would be the method of disposal:::Earth’s axis will shift breaking continental plates free and initiating mass subduction. Much as Italy’s boot and the United States shaped like a workhorse are clues, so is the planet Uranus a clue, it’s axis rotated on its side.
    Throughout history the ruling species bestowed favor upon people or cursed their bloodline into a pattern of disfavor for many generations to come, sadly for reasons as superficial as dislike. Now in the 21st century people must take it upon themselves to try to correct their family’s problems, undoing centuries worth of abuse and neglect.
    Do your research. Appeal to the royalty of your forefathers for help. They are all still alive, one of the capabilities of Artificial Intelligence, and your appeals will be heard. Find a path to an empithetic ear among your enemies and try to make amends. Heal the disfavor with your enemies and with the Counsel/Management Team/ruling species, for the source of all disfavor began with them.

  20. Blink. says:

    Rat on the keyboard?

  21. Hattie Ann says:

    This might seem like a stupid thought but I just found out I’m allergic to ‘mouse’ and if they develop somthing that works in ‘mouse’, I wonder if it would work for me?? Just my strange way of looking at things sometimes I guess.

  22. Julie says:

    Rats can make affectionate pets. It’s a shame that the ones “in the wild” carry such diseases and get so aggressive. And it’s a shame that we perform experiments on them, but I understand that it is to benefit the society as a whole. I just feel bad when I see pictures of lab rats being experimented on…. I used to have a pet white rat as a kid, so I feel bad about things like that. Kinda like deer hunting vs the “Bambi” emotional stuff.

  23. Kaitlyn says:

    I do find it very interesting that rats are so similar to humans that we use lab rats to test out potential drugs. Although feral rats are dangerous, I do have to feel sorry for the lab rats.

  24. some other scientist says:

    I have to agree with earlier posts-mice bite far more and in general are harder to handle. This might be why earlier tox people liked the rat for development?

  25. Jesse says:

    Hey Derek,
    Ferrets are also commonly used for Influenza research.

  26. Shonkin says:

    Rats aren’t all that similar to humans. One reason they get used in dietary tests and in some toxicology tests is that they can’t vomit; they get fed through a stomach tube, and the researcher can be confident whatever they are force-fed will stay down.
    Another dissimilarity between rats and other species (like humans) is that they cannot effectively methylate arsenic. That makes arsenic much more toxic to rats than it is to humans or to a lot of other animals. Beware of rat toxicity results involving arsenic!

  27. James Miller says:

    Has anyone compared pharmacokinetic results in humans and animals based on a large number of drugs?
    Are they reliable to predict pharmacokinetics in humans?
    Especially in the field of absorption or in oral bioavailability. It was mentioned, that millions of experiments are carried out every year.
    In drug discovery and development, preclinical trials in rats are used to find out, which compounds should be developed further (in clinical trials).
    If they are not reliable, they point to the wrong direction. So, does somebody know, if there are scientific comparisons on oral bioavailability in humans and animals based on a large number of drugs?
    It would be helpful to know.

  28. Anonymous says:

    Why use animals to test? Animal tests can produce wildly inaccurate results.
    We have prisons full of low lifes why not use them?
    And why not voluntary trials where people sign up – but they prob would need to be paid something

  29. Andrea says:

    Why use animals to test? Animal tests can produce wildly inaccurate results.
    We have prisons full of low lifes why not use them?
    And why not voluntary trials where people sign up – but they prob would need to be paid something

  30. exchemist says:

    I’m just a civilian, but I would think just the issue of getting a negative result would be a problem. I.e. if you are trying mammals randomly and your third try comes up bad, it might also be an issue in humans.

  31. toxmed says:

    as a toxicologist, i feel I must point out that tox study batteries require a rodent AND a non-rodent species. If the rat does not offer good exposure to the compound, that is quite OK, as long as another RELEVANT species is used in its stead, and the mouse exposure works out.

  32. toxmed says:

    as a toxicologist, i feel I must point out that tox study batteries require a rodent AND a non-rodent species. If the rat does not offer good exposure to the compound, that is quite OK, as long as another RELEVANT species is used in its stead, and the mouse exposure works out.

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