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Microsoft word - cyclosporine case study

For more information please contact:
Dr Roley Davis, Business Development Director Case Study – Metabolites of Cyclosporin A
Introduction:. Cyclosporin A (Csp A; Sandimmune®) is a natural product produced by the fermentation of the
fungus Tolypocladium inflatum and is used extensively as an immunosuppressant. Its primary route of metabolism
is via hepatic cytochrome P450s of the 3A family, the major human metabolites of cyclosporin being two different
hydroxylated (AM9 & AM1) and an N-demethylated derivative (AM4N). Here we demonstrate that using microbial
biotransformation, human and human-like metabolites of API’s can be produced efficiently and at a scale that
facilitates not only bioanalytical applications, but toxicological, pharmacological, structure-activity relationship and
other studies.
Screening and confirmation: a panel of microbial species was screened for the potential to metabolise
cyclosporin A by adding 100mg/L substrate to growing cultures. Several strains were seen to produce metabolites
of interest, including mono- & di-hydroxylations, and N-demethylated derivatives, as well as combinations thereof.
In all, nine putative metabolites were observed. Analysis of the products using HPLC-MS indicated the likely
presence of AM9 and other hydroxylated metabolites among them.
R = H Cyclosporine A
Fig 1: Structure of Cys A indicating biotransformation to the AM9 metabolite, and chromatogram of some of the
Scale up and purification: In order to produce quantities of metabolite sufficient for NMR analysis and for
pharmacological/toxicological testing, the metabolite producing cultures were scaled up to a volume of 2.25L with
an increased concentration of 200mg/L of substrate. Cultures were harvested at 24hrs and were sufficient for the
isolation and purification of approx. 40mgs of the desired AM9 metabolite. Most of the other observed metabolites
were of sufficient concentration in the culture medium to have been isolated in 2-30mg quantities if this had been
Summary: Human and human-like metabolites of natural products can be efficiently produced using microbial
biotransformation. Using this approach facilitates not only the production of metabolite reference standards, but
allows for the production of other compound derivatives to determine structure activity relationships, discover new
or improved activity and create intellectual property.
Testimonial: “Hypha’s biotransformation service made available materials important to support
our innovative drug delivery and development programs. Their expertise and professionalism
made them easy to work with and we would gladly do so again if the occasion arises.”
Dr Ivan Coulter, CEO
Sigmoid Pharma


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Ara-ct/mri patient history form

Austin Radiological Association Patient History/Contrast Form HAVE YOU HAD ANY PREVIOUS IMAGING STUDIES OF THE BODY PART BEING EXAMINED TODAY? HAVE YOU EVER HAD? Previous imaging that required an injection of contrast media/dye? If yes, did you have a reaction or experience any difficulties due to any imaging contrast/dye injection? Surgery to the part of your body being exami

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