One-Stop Metabolite Shop
Production of multi-gram amounts of a dihydrodiol metabolite using liver microsomes
Dihydrodiol metabolites can be formed from the action of CYP enzymes on aromatic systems to form an epoxide which is then acted on by microsomal epoxide hydrolase to yield a stable dihydrodiol. Following screening of a client compound, it was evident that the dihydrodiol metabolite sought was best produced using microsomes of a particular species from a specific supplier source. Multiple batches of scale-up incubations and purifications were undertaken at a 30% conversion yield to deliver hundreds of milligrams of material to the client at > 95% purity by LC-ELSD.
Production of an N-glucuronide by liver S9 tissue
A client project involved the preparation of 3 major N-glucuronides and 1 minor N-glucuronide. The parent drug was screened in Hypha’s chemical screens and microbial panels, as well as multi-species liver S9 supplemented with UDPGA cofactor, and resulting extracts matched against a mammalian plasma reference sample. The chemical screening conditions resulted in the synthesis of two of the major glucuronides and the minor glucuronide. Microbes could also produce the same glucuronides. However, one of the major N-glucuronides could only be produced by liver S9 fractions.
Chemical synthesis and mammalian biotransformation enabled all four of the glucuronides to be synthesised and purified for the client.
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There has been a notable increase in metabolism of new drug candidates through non-CYP phase I pathways such as those mediated via aldehyde oxidase (AO).1 Further, mixed AO/P450 substrates may be subject to metabolic shunting, an important consideration during toxicology and DDI assessment of these drugs.2 Access to metabolites may thus be important to consider for drugs with mixed metabolism.
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.
Hypha Discovery has been a valuable metabolite ID partner. Hypha have provided biotransformation, metabolite purification and structure elucidation answers to some of our most challenging metabolism and metabolite ID problems. We really appreciate the breadth of expertise available at Hypha Discovery and will definitely reach out for future work.
Director of DMPK
US 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.