V. Veeravalli, Ranjeet P. Dash
Dec 13, 2019
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Influential Citations
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Journal
Chemical research in toxicology
Abstract
Tofacitinib is an orally administered medication with a mechanism of action that involves JAK1, JAK2, JAK3 and TYK2 pathway inhibition. There is an increasing interest in the use of this drug in the management of psoriatic arthritis, following its success and wide use as an approved treatment option for patients with rheumatoid arthritis. Recently, Guo et al. (2019) reported a well-designed and executed in vitro metabolism study entitled, "Tofacitinib is a Mechanism-Based Inactivator of Cytochrome P450 3A4" to elucidate the mechanism-based inactivation of tofacitinib by trapping reactive metabolites generated in microsomal incubations. The results identified tofacitinib as a concentration-, time-, and NADPH-dependent irreversible inhibitor of CYP3A4 where glutathione (GSH) and superoxide dismutase/catalase offered minor or little protection against the CYP3A4 inactivation. Of the epoxide and α-keto-aldehyde intermediates of tofacitinib were trapped and characterized in microsomal incubations, and aldehyde intermediate was proposed to be the key for the CYP3A4 enzyme inactivation. While the present data will promote more scientific thinking and rationalization to possibly explain the mechanistic basis of the side effects induced by tofacitinib, especially liver injury, there are certain aspects of the data which need introspection to understand and validate the proposed concept. The intent of this letter is to highlight the concerns of undermining the significant contribution of the epoxide intermediate as well as the role of glutathione trapping process in the enzyme inactivation. Analysis of the results inferred that the observed higher enzyme activation by tofacitinib as compared to analogue 2 (that forms only aldehyde intermediate) could be because of its ability to generate both epoxide and aldehyde. Secondly, it has been inferred that the nucleophilic agent GSH exhibited limited ability to attenuate tofacitinib-induced CYP3A4 inactivation. This could be due to the absence of cytosolic glutathione-s-transferases (GST) for GSH adduct formation in the metabolic process, as cytosolic GSTs are functionally different from microsomal GSTs. Furthermore, in Scheme 2, it has been depicted that the epoxide intermediate conjugates with NAC to form two isomers. However, the possible isomers have been named as M1/M2/M3 indicating that there is a chance of formation of three isomers. Thus, Scheme 2 needs clarification for the readers who would be interested to know the probable mechanism of formation of three isomers.