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Elucidating the Mechanism of Tofacitinib Oxidative Decyanation. | LitMetric

Elucidating the Mechanism of Tofacitinib Oxidative Decyanation.

Drug Metab Lett

Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way MS 412a, South San Francisco, CA 94080 USA.

Published: October 2017

AI Article Synopsis

Article Abstract

Background: Tofacitinib is known to generate two metabolites M2 (alcohol) and M4 (acid), which are formed as the result of oxidation and loss of the nitrile [1].

Method: Systematic in vitro investigation into generation of M2 and M4 from tofacitinib.

Results: In vitro using human liver microsomes, we found a new geminal diol metabolite of tofacitinib (MX) that lost the nitrile. MX was further reduced or oxidized to M2 (alcohol) and M4 (acid), respectively by enzymes such as aldo-keto reductase 1C1, aldehyde oxidase and possibly CYP3A4. Stable label studies using H2 18O and D2O suggested the source of oxygen was from water in the media. This was due to rapid water exchange with MX in the media prior to reduction to M2. In case of deuterium, one was incorporated in M2 and this was mainly as a result of tofacitinib rapid exchange of two deuterium atoms from D2O onto methylene position. After formation of MX, there was one deuterium that no longer exchanged with water and therefore retained in M2 for further reduction.

Conclusion: The proposed mechanism involved the initial oxidation by P450 at the α-carbon to the nitrile group generating an unstable cyanohydrin intermediate; followed by the loss of the nitrile group to form a new geminal diol metabolite (MX).

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Source
http://dx.doi.org/10.2174/1872312810666160427104954DOI Listing

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