# Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2

## TL;DR

Crizotinib reduces tramadol metabolism in rats by inhibiting specific liver enzymes, which could lead to higher tramadol levels and potential side effects.

## Contribution

This study identifies crizotinib as a non-competitive inhibitor of CYP2D1 and CYP3A2, affecting tramadol metabolism in both in vitro and in vivo models.

## Key findings

- Crizotinib showed the highest potency in suppressing tramadol metabolism in rat and human liver microsomes.
- Co-administration of crizotinib increased tramadol's AUC in vivo, indicating reduced metabolism.
- CYP2D1 and CYP3A2 activities and total cytochrome P450 abundance were reduced in rat liver with crizotinib.

## Abstract

To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction.

Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed.

Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group.

Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.