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The metabolism of drugs and other xenobiotics often involves biotransformations of molecules to less lipophilic, more water-soluble, and more quickly eliminated products. This typically occurs in two phases:
  • Phase I drug metabolism: polar groups are added or exposed (e.g. hydroxylation)
  • Phase II drug metabolism: conjugation of molecules to polar ionic groups (e.g. glucuronidation)
The phase I metabolism poster below shows examples of phase I metabolism of drugs and other xenobiotics. It includes examples from the most common types of phase I metabolism biotransformations which include:
  • Oxidation reactions (mediated by P450s, FMOs, ADH, AO, XO, MAO)
  • Reduction reactions (mediated by NTRs, GRX, TRX, GSH, AZORs, CBR)
  • Hydrolysis reactions (mediated by EH, CE, and various other peptidases, endopeptidases, and proteases)
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The list of phase I metabolism examples below should give the reader a general overview of how phase I metabolism can impact drugs, and why phase I metabolism is important.

Aliphatic Hydroxylation: Norketamine
Ketamine, a dissociative anesthetic, has recently emerged as a novel antidepressant. Norketamine is the N-demethylated major metabolite of ketamine. Aliphatic hydroxylation of norketamine at the six position results in hydroxynorketamine (HNK). Ketamine is racemic and forms several HNK stereoisomer metabolites. The HNK metabolites of ketamine do not produce anesthetic effects and were long thought to be inactive; however, …

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“Phase I metabolism is not just about CYPs,” says Dr. Julia Shanu-Wilson of Hypha Discovery. “An impressive range of reactions are catalyzed by a number of enzymes, and this article is a useful reminder of this.”
“Biotransformation “networks” also result in impressive examples such as seen in the metabolism of ozanimod where no single enzyme system predominates. In fact, ozanimod is metabolised by phase 1 reactions that not only include multiple CYPs, but also ADH/ALDH, MAO-B and CBR, as well as ring opening and scission by gut microflora. There’s also phase 2 metabolism at play featuring NAT2 and UGTs. Active metabolites also result from biotransformation of ozanimod where, for instance, a long-lived MAO-B metabolite of a CYP metabolite is also an active metabolite.”
“An understanding of the biotransformation of a drug provides opportunity not only for addressing any safety concerns but also provides an opportunity for SAR and unearthing metabolites with interesting properties distinct from those displayed by the parent drug.”
Hypha Discovery is a specialist CRO supporting pharma companies worldwide through production, purification and identification of metabolites and late-stage drug derivatives.
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