MetID of gut metabolites
Microbiota in the human gut are increasingly being considered as a virtual organ which plays a critical role in drug metabolism. The majority are obligate anaerobes from the genera Bacteriodes, Clostridium, Lactobacillus, Escherichia and Bifidobacteria, together with an assortment of other microorganisms.1 The role of this “organ” in the metabolism of some drugs is complicated by variability in the individual composition of microbial species in the gastrointestinal tract, potentially causing differences in the drug response.
As well as activation of pro-drugs, direct microbiome-derived metabolism can lead to deactivation, reactivation through enterohepatic recycling, or biotransformation of a drug to a toxic metabolite.
Screening and scale-up service
Hypha’s human faecal pool can be used to screen for reduced metabolites of drugs, as exemplified with control compounds sulfasalazine and nizatidine. In the case studies illustrated, drugs were incubated in human faecal material derived from several mixed sex donors under oxygen depleted conditions. The reduced metabolites were easily detected by LC-MS.
Human faecal incubations can be scaled up to provide material for purification of metabolites prior to structure elucidation by cryoprobe NMR.
Find out more about Hypha’s gut metabolite screening service.
Reference
Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017 Jan;179:204-222. doi: 10.1016/j.trsl.2016.08.002.
Fecal metabolism of ozanimod
A further study was completed looking at the gut metabolites of ozanimod in Hypha’s system. Mechanisms involve reductive cleavage followed by hydrolysis resulting in oxadiazole ring scission. All reported metabolites were observed.
An interesting article on the impact of the biotransformation of ozanimod was featured in Drug Hunter, including the impact of gut microbiota in generating a major inactive metabolite (RP101124). This metabolite was discovered during an in vivo 14C-ADME study in rats, where a lag time was observed before its appearance in circulation.
