Case Studies
Case Studies and Client Projects
Latest Case Studies
In this case study, all of the main human metabolites of cyclosporin A were produced using microbes in Hypha’s biotransformation panels, and by using PolyCYPs® enzymes. Additionally we are able to form novel microbial-derived metabolites.
Access to multiple metabolites needed to support clinical development is not always straightforward, and can sometimes mean that more than one technique needs to be applied to fulfil requirements. In one such project, a US pharma client required > 200 mg of three metabolites of a drug; an N-glucuronide (M1), an indirect O-glucuronide (M2b) and a hydroxylated metabolite (M8b). As part of this project, multiple components of Hypha’s one-stop metabolite shop were employed, including chemical synthesis, microbial biotransformation as well as purification and structure elucidation by NMR.
If clearance mechanisms of the test drug results in sufficient quantities of the major metabolites in biological material such as faeces or urine, purification and subsequent identification of metabolites from such matrices is possible. One such project undertaken at Hypha resulted in tens of milligrams of the R- and S-O-glucuronides of carisbamate, a neuromodulator developed by SK Life Science, which were purified to >95% purity from 150 ml of urine using a three-step purification method.
Metabolites of some agrochemical products such as pesticides and herbicides possess greater plant or mammalian toxicity compared to the parent compound, thus necessitating a need for their identification, study and provision of analytical reference standards to meet regulatory requirements. Where a synthetic route is challenging, or the identity of a metabolite is unknown, creation of metabolites by microbial biotransformation is often a successful alternative due to similarities of xenobiotic metabolism in mammals, birds, fish, soil, and to some extent, plants.1 Furthermore, biocatalysis affords aromatic and aliphatic site-selectivity as well as regiocontrol of aromatic hydroxylation.2
The FDA’s 2020 MIST guidance states that phase 2 conjugates are generally pharmacologically inactive, however where a potentially toxic conjugate, such as an acyl glucuronide is formed, additional safety assessments may be needed. Idiosyncratic drug toxicity of carboxylic acid-containing drugs can be caused by the formation of reactive acyl glucuronides, which have the ability to directly acylate proteins and undergo intramolecular rearrangement producing reactive aldehydes leading to protein glycation.
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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.