Related Experiment Video

Updated: Jan 20, 2026

A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
07:38

A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s

Published on: September 25, 2017

10.7K

Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4

Xiucai Guo, Wei Li, Qingmei Li

  • 1State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province , Guizhou Medical University , Guiyang , Guizhou 550004 , P. R. China.

Chemical Research in Toxicology
|August 16, 2019
PubMed

Insights

Tofacitinib (TFT) irreversibly inhibits CYP3A4, a key enzyme in drug metabolism. This mechanism-based inactivation, driven by an aldehyde intermediate, is crucial for understanding TFT

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Enzyme Kinetics

Background:

  • Tofacitinib (TFT) is an oral Janus kinase (JAK) inhibitor used for rheumatoid arthritis.
  • Understanding drug-drug interactions and metabolic pathways is vital for safe and effective drug use.

Purpose of the Study:

  • To investigate the mechanism by which Tofacitinib (TFT) affects Cytochrome P450 3A4 (CYP3A4) activity.
  • To characterize the interaction between TFT and CYP3A4, including the kinetics and intermediates involved.

Main Methods:

  • Incubation of recombinant CYP3A4 with TFT to assess enzyme activity loss.
  • Kinetic analysis to determine inactivation rate (k_inact) and inhibition constant (K_I).
  • Trapping and characterization of TFT metabolites (epoxide and aldehyde) using microsomal incubations.

Main Results:

  • TFT demonstrated concentration-, time-, and NADPH-dependent inactivation of CYP3A4, with observed irreversibility.
  • Significant loss of CYP3A4 activity (>70%) occurred upon incubation with TFT (200 μM).
  • An aldehyde intermediate of TFT, primarily formed by CYP3A4, was identified as the likely cause of enzyme inactivation.

Conclusions:

  • Tofacitinib (TFT) is a mechanism-based inactivator of Cytochrome P450 3A4 (CYP3A4).
  • The inactivation is mediated by an aldehyde metabolite of TFT, highlighting a significant drug-metabolizing enzyme interaction.
  • Findings are critical for predicting and managing potential drug-drug interactions involving Tofacitinib.

More Related Videos

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c07:42

Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c

Published on: June 29, 2011

17.8K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.7K

Related Concept Videos

X-Inactivation01:58

X-Inactivation

The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
41.6K
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
11.2K
Reaction Mechanisms03:06

Reaction Mechanisms

Chemical reactions often occur in a stepwise fashion, involving two or more distinct reactions taking place in a sequence. A balanced equation indicates the reacting species and the product species, but it reveals no details about how the reaction occurs at the molecular level. The reaction mechanism (or reaction path) provides details regarding the precise, step-by-step process by which a reaction occurs.
For instance, the decomposition of ozone appears to follow a mechanism with two steps:
30.5K
Mechanical Protein Functions01:58

Mechanical Protein Functions

Proteins perform many mechanical functions in a cell. These proteins can be classified into two general categories- proteins that generate mechanical forces and proteins that are subjected to mechanical forces. Proteins providing mechanical support to the structure of the cell, such as keratin, are subjected to mechanical force, whereas proteins involved in cell movement and transport of molecules across cell membranes, such as an ion pump, are examples of generating mechanical force. 
5.5K
The Quantum-Mechanical Model of an Atom02:45

The Quantum-Mechanical Model of an Atom

Shortly after de Broglie published his ideas that the electron in a hydrogen atom could be better thought of as being a circular standing wave instead of a particle moving in quantized circular orbits, Erwin Schrödinger extended de Broglie’s work by deriving what is now known as the Schrödinger equation. When Schrödinger applied his equation to hydrogen-like atoms, he was able to reproduce Bohr’s expression for the energy and, thus, the Rydberg formula governing hydrogen spectra.
56.6K
Mechanism of Conjugation01:19

Mechanism of Conjugation

Bacterial conjugation is a mechanism of horizontal gene transfer that enables the exchange of genetic material between bacterial cells through direct contact. This process is facilitated by a donor cell carrying a conjugative plasmid, which encodes genes necessary for pilus formation, DNA replication, and transfer. The conjugative plasmid plays a central role in initiating and executing the transfer of genetic material.The tra region of the conjugative plasmid encodes proteins responsible for...
870