Unusual biotransformation reactions

Unusual biotransformation reactions uncovered by scientists at Genentech 

This compilation of 10 case studies arising from work done at Genentech gives an insight into some interesting and unusual biotransformation reactions at play in drug metabolism, resulting in the formation of novel metabolites. Emphasis is placed on understanding observations in terms of reaction mechanisms.

Reactions discussed involving small molecule drugs include:

  • Amide hydrolysis by aldehyde oxidase to a major human circulating aniline metabolite
  • FMO mediated para phenyl ring oxidation resulting in elimination of fluorine at this position. The quinone imine intermediate could be trapped by N-acetyl cysteine to form a stable thiol conjugate, but not with glutathione due to size limitation in the FMO active site.
  • Formation of a polar rodent specific metabolite with addition of 621 Da arising from conjugation of ribose to a pyrazole moiety.
  • CYP1A1 mediated intramolecular rearrangement of an aminoazepane moiety to a metabolite with the same elemental composition but which was chromatographically distinct from the parent drug. Unexpected expansion of the active site cavity of CYP1A1 enabled accommodation of the substrate.
  • CYP mediated decyanation releasing cyanide which was converted to thiocyanate in vivo. This was a minor pathway in humans and was thought not to pose any safety concerns.
  • CYP2C19 catalysed ring formation resulting in 2 unusual metabolites through different routes, one by creation of a new pyrazol-3-ol ring and the other through formation of an imidazole-2-one ring via an amide intermediate. The metabolite with the new pyrazol-3-ol ring and the glucuronide arising from this were estimated to reach 10% of parent in clinical studies.
  • CYP mediated pyridine ring cleavage via aldehyde intermediates.
  • Ineffective inactivation of CYP2C9 by the pan CYP inhibitor 1-Aminobenzotriazole (ABT) due to the ability of the large active site of CYP2C9 being able to accommodate multiple ligands and the consequent binding of ABT to a distal “non-productive” pocket.

Khojasteh, C., Sodhi, J.K., Halladay, J. et al. The past decade of Genentech experience in elucidation of novel reaction mechanisms in drug metabolism. Med Chem Res (2023).

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