The involvement of FMOs in human metabolism of drugs is suggested to be underestimated (Phillips & Shepherd, 2016) and can offer an attractive route of elimination due to a lower tendency than CYPs to be inhibited or induced, resulting in a lower DDI potential. FMOs are a family of microsomal NADPH-dependent enzymes that catalyse the oxygenation of nucleophilic heteroatoms, particularly nitrogen, sulfur and phosphorus moieties. N-oxide and S-oxide formation represent the major FMO-mediated mechanisms, and particularly good substrates for FMOs include primary and secondary amines. Many drug substrates of FMOs contain tertiary amines (which are oxygenated to form the N-oxide), or sulfides, which are S-oxygenated to the sulfoxide. Most products of FMO metabolism are non-toxic however some of the N-hydroxylated products of primary and secondary amines can inhibit CYPs and may have toxic effects.
In humans, there are 5 functional FMOs which exist in different tissues in humans.
Notably FMOs are thermally labile, especially in the absence of NADPH.
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Formation of N-oxide metabolites is one of the major pathways for metabolism of tertiary nitrogen-containing drugs. Some N-oxide metabolites have similar or greater pharmacological activity to the parent drug and thus require exposure assessment. They can also be unstable and can revert to the parent drug.1 Conversion of an N-oxide metabolite back to the parent in vivo is a well- known phenomenon which may result in an altered tissue distribution of the metabolite and parent drug, such as that proposed for tamoxifen,2 or cause adverse reactions as reported for soratenib.3 In the lab, it is possible to reduce the potential for conversion of N-oxide metabolites to the parent through careful sample handling, as described for the clinically-significant metabolite loxapine N-oxide.4
In this paper, authors from Hypha and Incyte Corporation discuss the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design.
In Chapter 4 of the book on “Identification and quantification of drugs, metabolites, drug metabolizing enzymes and transporters”, Hypha authors summarise the different methods employed for producing metabolites of drugs, illustrated with representative examples from the literature and work undertaken at Hypha. The chapter also includes a discussion and examples of the use of NMR spectroscopy for structure elucidation of metabolites.
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Hypha’s One-Stop Metabolite Shop enables synthesis, purification and characterization of all the main types of mammalian phase 1 and 2 metabolites.
“We approached Hypha Discovery for the preparation of 10-50 mg quantities of two API metabolites that had proven difficult to synthesise chemically. The project was highly successful, combining beautifully executed multi-disciplinary science with clear and responsive communications; the collaboration was a genuine pleasure. I have no hesitation in recommending Hypha to others for metabolite generation and scale-up.”
Head of CMC
UK Pharma Company
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Hypha Discovery is a UK-based CRO supporting pharmaceutical and agrochemical companies worldwide through the production of metabolites and new derivatives of drugs and agrochemicals in discovery and development.