Non-CYP Metabolism

Non-CYPs play an important role in the metabolism of many drugs. The emerging importance of UGTs in DDIs is highlighted by their inclusion in the 2012 versions of the FDA and EMA DDI guidances. Non-CYP enzymes include:

  • UGT
  • Flavin monooxygenase (FMO)
  • Monoamine oxidase (MAO)
  • Aldehyde oxidase (AO)
  • Xanthine oxidase (XO)

How Absorption Systems approaches non-CYP inhibition testing?

UGT Inhibition
We incubate probe substrates with individual human recombinant UGT enzymes, with and without test article. The rate of appearance of a specific probe metabolite is compared with that of the solvent control without test article to assess inhibition of a given UGT by a test article.

Why non-CYP enzyme phenotyping?

Knowing how a drug candidate is eliminated by the human body is important in understanding the potential for drug-drug interactions. Drug metabolism pathways and the relative contributions of different enzymes are evaluated through enzyme reaction phenotyping studies.  Depending on the enzyme(s) of interest, these studies are performed using liver,  cyotosol, or recombinant enzymes.

How Absorption Systems approaches non-CYP enzyme phenotyping:

UGT Phenotyping
Incubation of test article with human recombinant UGT enzymes. Disappearance of test article is compared to that of a control treatment (no UGT enzymes present) in order to assess the contribution of a given UGT to the test article’s metabolism

MAO/FMO Phenotyping
Incubation of test article with human recombinant MAO/FMO enzymes. Disappearance of test article is compared to that of a control treatment (no MAO/FMO enzymes present) in order to assess the contribution of a given MAO/FMO to the test article’s metabolism

AO/XO Phenotyping
Incubation of test article with human liver cytosol and specific chemical inhibitors. Disappearance of test article is compared to that of a control treatment (no inhibitor) in order to assess the contribution of AO or XO to the test article’s metabolism.