You’d think that we would know all about where our drug compounds go in the body when a patient takes them, but that’s not quite the case. We know about a lot of the general processes of absorption and distribution, and we know some of the main places to look. All of these reveal subtleties on closer inspection, naturally – you might (for example) cite some number as representing the blood level of a particular compound at a particular dose and time point, but what about free compound versus compound bound to plasma proteins? How free is “free”? Which plasma proteins – serum albumin or something else (lipoproteins, glycoprotein, globulins)? What about the compounds that actually work their way into the interiors of red blood cells, or the ones that stick to their outer membranes? The ones that bind to platelets? Beyond just the blood, there are compounds that end up in the lymphatic fluid, compounds that detour into the bile after an oral dose and reappear in the gut after that cycles around, compound that partition into lipid tissue and slowly diffuse out of those for weeks or months (these often partition into the brain tissue, since the white matter of the nervous system qualifies, too), and many more.
Here’s one that you might not have thought of, though: accumulation of compounds inside gut bacteria. That paper looks at fifteen various drugs across 25 strains of gut bacteria, and finds a whole range of interactions. These were measured as depletion of the drug in the culture medium, and about half the cases seem to be not metabolism by the bacteria, but simply intracellular storage. With these, after cell lysis the original drug concentration could be restored from the total culture. Two drugs, duloxetine (an antidepressant) and rosiglitazone (an antidiabetic) were accumulated to a large degree across numerous species. Duloxetine could even be detected by NMR of washed bacteria that were transferred to phosphate-buffered saline solutions. Other compounds, such as the asthma medication montelukast, were degraded by some species and accumulated by others.
You might imagine that this bioaccumulation would have an effect on bacterial growth, but that didn’t seem to be the case in a general sense. A closer look, though suggested that it did affect metabolism, with altered metabolite profiles in a number of accumulating species. The paper also tried some experiments with culture containing multiple species, looking at what occurred once duloxetine was added. There were some dramatic changes in the abundance and ratios, apparently due to “cross-feeding” events as some bacteria secreted particular metabolites that boosted those around them.
So this gives us at least three ways that pharmaceuticals can interact with gut bacteria: by direct metabolism and transformation of the drug, by lowering its concentration without producing a drug metabolite, and by altering the microbiome through changes in bacterial metabolism. Microbiome studies are notoriously complex and difficult, and a lot of hard-to-interpret data have come out of them. And now we have yet more ways that things can get tangled up!
