tx9b00141_si_001.pdf (570.31 kB)
Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4
journal contribution
posted on 2019-08-25, 15:13 authored by Xiucai Guo, Wei Li, Qingmei Li, Yan Chen, Guode Zhao, Ying Peng, Jiang ZhengTofacitinib
(TFT) is an oral JAK inhibitor which has been approved
for the treatment of moderately and severely active rheumatoid arthritis.
TFT was found to show concentration-, time-, and NADPH-dependent inhibition
of CYP3A4, and irreversibility of the inactivation was also observed.
Incubation (40 min, 37 °C) of recombinant CYP3A4 with TFT at
200 μM resulted in >70% loss of CYP3A4 activity. Estimated kinact and KI were
0.037 min–1 and 93.2 μM, respectively. GSH
and superoxide dismutase/catalase revealed minor or little protection
against the CYP3A4 inactivation. Furthermore, ketoconazole attenuated
TFT-mediated CYP3A4 inactivation. Epoxide and α-keto-aldehyde
intermediates of TFT were trapped and characterized in microsomal
incubations, respectively. The aldehyde intermediate is believed to
be the key for the enzyme inactivation. Multiple P450 enzymes, including
CYPs2C19, 3A4, 2D6, and 1A2, participated in the metabolism of TFT
to the epoxide, while the formation of the aldehyde was mainly catalyzed
by CYP3A4. In conclusion, TFT was proven to be a mechanism-based inactivator
of CYP3A4.