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Pharmacokinetics

Gut Bacteria, Pitching In

When a patient takes an oral dose of a drug, you can picture it as being a little like one of the those Japanese pachinko machines, where a ball drops into a maze of complicated bouncing paths on its way to the bottom. There are a lot of things that happen once a pill hits the gut, the broad features of which process are described by the acronym ADME (absorption, distribution, metabolism, and excretion). The metabolism part, for example: there are many chances for one enzyme or another to alter the structure of your active drug. There are digestive fluids in the stomach and intestine, enzymes in the gut wall, enzymes in the blood plasma once a compound is absorbed through it, and a ton of enzymes in the liver, which is of course the first stop for anything absorbed out of the intestine. A drug’s structure can get hydrolyzed, oxidized, dealkylated, hydroxylated, conjugated, reduced, and more, and most pharmaceuticals produce a spray of such metabolites that can be picked up in the blood, urine, and so on. Some of these will also be active against your drug’s original target, albeit with totally different half-lives and distribution. Some of them will totally lose that original activity, but will turn out to be active against other things entirely. Good luck tracking those down, and welcome to ADME!

It’s long been recognized that the gut bacteria can be another source of metabolic degradation, but this new paper from a team at Yale suggests that it’s even more wide-ranging than we’ve realized (commentary at Nature here). The authors did a pretty extensive survey: 271 known drugs against 76 different sorts of human microbiota. This is definitely the most systematic look at the issue yet, since many of the known examples are one-offs discovered in the clinic. It was done by a pooling strategy – the 271 drugs were spread out among 21 pools, such that each one was represented in four different groups, but shares any pool with another given drug at most twice. That gives you 3,840 interactions, measured in quadruplicate at 12-hour anaerobic incubation points.

For two-thirds of the drugs tested, the amount of the parent compound was reduced by at least 20% by at least one bacterial strain. So bacterial metabolism is not some odd exception – and given how variable the gut microbiome can be from person to person, you can see yet another source of the noise in human clinical data and medical practice. As was already well appreciated, nitro and azo functional groups were particularly labile (for many varieties of bacteria), but quite a few other things showed up as well. Bacteroidetes species, for example, were particularly good at amide and ester hydrolysis, but the whole range of chemical changes mentioned above were present in various cases. The paper goes on to a number of experiments with gnotobiotic (bacteria-free) mice, showing that colonization of their intestines with various bacterial strains can reproduce the in vitro effects on metabolite profiles, and the team also started to untangle some of the genetic signatures of the various metabolizing enzymes across the different species.

This paper last year showed that a number of (non-antibiotic) drugs can have effects on the gut microbiota in turn, and it’s also been shown that treatment with metformin in Type II diabetes patients alters their gut bacterial population, and in a way that actually potentiate’s the drug’s effects. So all this comes together into a coherent (if wildly complicated) story. The drugs are affecting the bacteria, the bacteria are affecting the drugs, and both of those are affecting the patients and their responses. We have quite a ways to go!

29 comments on “Gut Bacteria, Pitching In”

  1. luysii says:

    Well maybe you aren’t what you eat after all

    1. John Wayne says:

      You are what is helping you eat?

    2. RandomWok says:

      Welcome to the chemical casino. No watchmakers (blind or sighted) required. It’s all probability and outcome.

  2. Day man, fighter of the night man says:

    Really cool study. Do they provide rationale for why the measured metabolism of drugs in bacterial culture after 12h? I’m trying to evaluate how well their model might apply to metabolism of drugs by bacteria in the gut. How well do the culture conditions replicate what happens in intestines. I imagine that bacteria concentration in culture, and as a result the metabolic enzymes they make are higher in culture than in intestines, so the observed metabolism may be higher than what is physiologically relevant. The dilitiazem/mouse data maybe a good place to start to look at this.

    The end of the discussion is interesting, but seems a bit far reaching:
    “This study provides a mechanistic understanding of microbiome drug metabolism that may enable rational strategies aimed at manipulating individuals’ microbiota to beneficially alter metabolic microbiome–host interactions.”

  3. Emjeff says:

    Well, guess I’ll get ready to start doing drug interaction studies with different bacteria for the FDA.

  4. Mike says:

    Don’t most drugs get absorbed by the first part of the small intestine where microbiome load is relatively small? Most of the microbiome is found in the large intestine and orally administered drugs usually don’t make it that far?

    Mike

    1. Day man, fighter of the night man says:

      I think your question is the same as the one that I had above.

    2. E. Patrick says:

      Only immediate release drugs, and even that is a generalization for BCS class 3/4 drugs (low permeability).

      Modified release drugs are specifically designed to stick around the GI track longer, through various mechanisms. Whether it is because the drug is better absorbed in the large intestine, or is degraded by the higher pH of the stomach, or you want the drug to continue dissolution for longer to extend the release – there are many formulations that will be impacted by the bacteria more than others.

  5. chemist in pieces says:

    in the news….
    “another biotech plant explosion in China”
    And people wonder why they threw everyone out of work here in the US.

    You can get guys to work 3 shifts out of one fume hood, the other 2 sleeping on grass mats somewhere in the building….with everyone exposed to the danger of the whole plant going up at any minute.

    And all for what? So pharma executives and shareholders can make more money than they know what to do with.

    What of all the taxes the people thrown out of work here were paying, so much for roads, bridges, schools, etc. etc.

    The rich could care less.

    1. x says:

      They probably could care less – I don’t suppose they’re all perfect sociopaths.

      Nevertheless, when those guys keep showing up to work and sleep in a death trap anyway, and smug pseudoeconomists over here tell us domestic job losses are our own fault for being too inefficient, the workers over there are actually happy because they can afford twice as much grass for their mats, and there’s nothing we can do to fix any of it anyway, and then we inevitably elect another slate of corrupt rich politicians who’ll give themselves and their biggest donors tax cuts while letting all the little guys twist in the wind…

      Well, humanity kind of deserves what it gets.

  6. Barry says:

    It had long been argued that “a gut is a gut, but livers vary a lot by species”. But we’re learning that that’s false. The fate of an oral dose will vary with microbiome within a species. Not only can gut microbes hydrolyze, oxidize, dealkylate, hydroxylate, conjugate, or reduced a drug substance. They present a PK compartment in which drugs may loiter, or vanish even if it’s not chemically modified.

  7. ScientistSailor says:

    …and there are people who think we can do away with animal testing for drug safety.

    or on the other hand you could argue that these data just add to the arguments that animal safety studies are irrelevant…

    1. Scott says:

      The appropriate response to anyone demanding an end to animal testing is, “So, you want to dose humans with a chemical that might actually prove toxic? There is a word for that, but I don’t think you’re going to like being called it.”

  8. Riffraff says:

    I don’t why this is surprise. Bacteria have esterases and reductases so that esters are hydrolyzed, nitro- and azo-group reduced.

    1. londonlad says:

      Yep. Not a surprise at all. But it’s good to show it experimentally. Most of the drugs for which they show these effects though are a little odd in their own way though – esters and nitro/azo groups are not on the list of most peoples go to functional groups.

  9. loupgarous says:

    I’ve learned the hard way that talking diclofenac (a god-send to arthritics) topically in a gel doesn’t prevent you from experiencing the symptom diclofenac’s oral form became infamous for – stomach ulcers.

    But if diclofenac enters the bloodstream from the skin efficiently enough to cause stomach ulcers, would it be reasonable to administer other drugs unevenly absorbed by the gut topically? The total percentage of the drug taken up might drop, but variability of uptake between patients might be less as well. Fentanyl is a treatment for intractable cancer pain best taken by transdermal patch for most patients.

    Could patch or other topical administration reduce uncertainty about the actual dosage the patient’s getting for drugs for which multiple pathways through the gut into the bloodstream exist?

  10. Anonymous says:

    I’ve been carrying around this schoolyard factoid for years so I might as well repeat it here: 30% to 60% of human fecal solids are (mostly dead) bacteria. Then there is undigested foods and fats. You can dig down deeper into the details (minerals, human cells shed from the stomach lining, etc.). I only wanted to highlight the huge amount of bacteria that is in, and comes out, of us. I don’t want to get into all that other s— in this post.

  11. Druid says:

    B. thetaiotaomicron is a compulsory anaerobe and resides mainly in the colon. Anyone who has experience of drugs which are poorly absorbed in the upper intestine and reach the colon knows just how variable their biavailability can be, and has probably tried very hard to avoid this situation ever after. One reason – gut transit time in people varies between 8 and 72 hours and most of that range is down to colon transit time. Does anyone have a good experience with colonic absorption that they can share?
    Perhaps microbial metabolism is another contribution to variability – certainly there is plenty still unexplained – but I can’t agree with the commentary when it says “Yet our knowledge of drug fate in the body is still rudimentary, despite a long history of studies in this area” and ends with “Adjusting the microbiota to suit our needs, including achieving individually tailored approaches to tackling drug metabolism, is probably where this field is heading”. Even if I thought you could do it, I wouldn’t let you mess with my microbiome.

    1. Anonymous says:

      I previously posted a K-12 schoolyard factoid about bacteria and feces. In the grad school schoolyard, routes of drug administration (IV, oral, inhalation, patch, etc.) were taught in seminars. We were told that drug companies mostly try to develop for oral administration because the large US market wants — demands — the convenience of popping a pill. More than one speaker said that, in Europe, suppositories are much more acceptable and a very common formulation. (Any EUs care to comment?) That bypasses the entire upper GI and goes straight to the rectum and, I assume, unless you have really long fingers, doesn’t even reach the colon, except, maybe, by diffusion.

      Is there a living microbiome in the rectum? (Most fecal bacteria are already DOA by the time they are there.) Is there much adsorption into the blood stream down there?

      1. Druid says:

        I have seen suppositories in a bathroom cabinet in France, years ago and for pediatric acetominophen treatment. This can be useful for medicines with a bad taste. I think it is the use on children which makes it seem normal in those countries.
        Len Brookes at Upjohn showed that insulin can be absorbed this way. Taken at night, the suppository melts and spreads across a large surface, and perhaps into the descending colon. There is a suggestion that the tight junctions are not so tight in the colon, proteases are not active there, and this route of administration can also avoid some first pass hepatic extraction as not all the venous drainage is via the portal vein. I have never known anyone worry about bacterial metabolism in the rectum when drugs are given in suppositories.
        Crack cocaine, anyone?

  12. anon says:

    I am just curious just as the way we have liver homogenates (mouse, human) that are commercially available and can be used for metabolic profile. Likewise, can we also get say gut homogenates? Its ready availability can mitigate issues related to metabolism. Though I understand that bio-flora distribution can be different for species.

  13. PhotoDeTox says:

    Besides in vitro microsomal and hepatocyte clearance, will we measure microbiomal clearance too?

  14. DTX says:

    To go back to the question where most drugs are absorbed: I’ve not seen a quantitative estimate, but I’d say most drugs are (it would be interesting to know which drugs are actually absorbed primarily in the large intestines). The role of the large intestine is mainly to absorb water.

    In contrast, the role of the small intestine is absorption. The surface area of the small intestines is amazing – ~250 m2. It’s about 7 meters long & with a good blood flow (which also facilitate absorption). The likelihood that I drug will pass the small intestines without absorption is very low (and if it passes the small intestines unabsorbed, it’s likely to stay so in the large intestines).

    Even enteric coated aspirin is absorbed in the small intestines (the coating prevents it from being absorbed by the stomach).

    Hence, Mike’s question about the low microbiome load in the small intestines is relevant.

    1. Druid says:

      I agree with you that a function of the colon is to absorb water, as far as the well/over-nourished world is concerned. But this neglects the role of the microbiome in the colon in a diet which is poor in fast nutrients and high in complex carbohydrates. Then the microbiome can assist in extracting calories from carbs which the mammal cannot digest. Even in the well-fed laboratory rat, the production of small fatty acids in the colon by bacteria and absorption through the colon wall is estimated to contribute 20% of the calory intake. They (acetic, propionic and isobutyric acids) also account for the smell.
      On the bad side, colonic bacteria are thought to be responsible for converting bile acids into carcinogens, and a possible reason why dietary fiber is protective against colon cancer. Give those bugs their favorite food.

  15. Me says:

    Maybe we need to develop a colon model for in vitro microbiota-induced PK. We should call it the arse-pipe.

  16. KN says:

    Oral administration might be the easiest way (to take the drug, not to develop it), but maybe it’s time to reconsider our obsession with it.

  17. Taco says:

    I think this work is really interesting, particularly in relation to Matt Redinbo’s work in microbiome-mediated colonic irinotecan reactivation. I think the microbiome is making unexpected contributions to PK that we’re only seeing now, but I ask this next question without being sarcastic or rhetorical: where does it matter? What are examples of _orally_ dosed drugs that have such narrow safety and efficacy margins that a 50% variation in oral exposure wouldn’t be detected in a well-designed dose-response study and accommodated by smart dosing options? I can think of one that fits that category (digoxin, which is a glycoside and maybe not surprising that the microbiome chews it up), but there must be others.

  18. David Edwards says:

    And articles like this are the reason I keep visiting Derek’s blog. Even though it’s been a long time since he posted anything in “Things I Won’t Work With”, which used to be a perennial stopping point for the latest explosive or corrosive wackiness, presented in Derek’s unique style.

    I’ve wondered intermittently in the past, how drugs manage to make it past the digestive system and its repertoire of chemical wrecking balls, though with relatively few substantive answers until now. The part about Metformin was particularly informative, given that this is now prescribed for my own type 2 diabetes, and probably explains why one develops an attachment to the bathroom porcelain one never wanted to once starting this drug!

    Of course, the details will probably require me to spend the next two decades studying the requisite biochemistry in depth to learn about, or possibly start a research programme of my own in order to fill in missing gaps in our knowledge, but Derek has once again exhibited a talent for making this topic comprehensible in a compelling manner. I’m also indebted to RandomWok for the “welcome to the chemical casino” line, which is as succinct a description of what’s going on as I’ve seen anywhere.

    Derek, you really should write more books. In my view, you have what it takes to the the Carl Sagan of medicinal chemistry.

    On a tangential note, the thought occurs to me that devoting one organ (i.e., the liver) to the business of being the body’s one-stop chemical laboratory, strikes me as somewhat “all eggs in one basket” from the standpoint of evolution. If that one organ fails, you’re in deep trouble. Scattering the functions around several subunits, whose individual failure wouldn’t be lethal to the organism, would seem to me to be a better approach (so much for “intelligent design”). Which makes me wonder why vertebrate evolution didn’t venture down that path instead. Again, a case of “it works well enough, so stick with it” – yet another example of evolution being survival of the sufficiently competent, as Darwin originally proposed before Galton got his eugenic mitts on the theory …

    1. John Francini says:

      Well, I think that the liver is an interesting compromise between the ‘all eggs in one basket’ and the ‘scattered functions in various subunits’ approaches. Why? The amazing ability the liver has to regenerate itself in the face of chemical onslaughts. If vertebrates had the ‘scattered functions’ model, but without the ability to regenerate, I could see situations arising where ingesting the wrong chemical could permanently ‘punch out’ one of those subunits, which would leave the organism to die the next time that chemical presented itself.

      Mind you, I’m personally far better at dealing with bits’n’bytes than with molecules’n’ligands, but it seems like a plausibly bad scenario…

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