METABOLOMICS REVEALS FIVE ENDOGENOUS BIOMARKERS IN HUMAN URINE AND
PLASMA TO PREDICT CYP2D6 ACTIVITY
Abstract
Background and Purpose: Individualized assessment of the activity of
cytochrome P450 2D6 (CYP2D6), a highly variable drug-metabolizing
enzyme, is performed through phenotyping during which a probe drug is
administered to measure the enzyme’s activity. In order to avoid any
iatrogenic harm (allergic drug reaction, dosing error) related to the
probe drug, the development of non-invasive tools for real-time
phenotyping of CYP2D6 could significantly contribute to the expansion of
precision medicine in clinical practice. This study focuses on the
identification of endogenous markers of the CYP2D6 enzyme in human
biofluids using a liquid chromatography (LC)-high-resolution mass
spectrometry (HRMS)-based metabolomics approach. Experimental Approach:
Data from a control session were compared to data from an inhibition
session. Before the latter, healthy volunteers (extensive and ultrarapid
metabolizers) received a daily dose of paroxetine 20 mg over seven days.
CYP2D6 genotyping and phenotyping, using single oral dose of
dextromethorphan 5 mg, were also performed in all participants. Key
Results: In CYP2D6 extensive and ultrarapid metabolizers (n = 37), mean
relative intensities of five features were significantly reduced during
the inhibition session compared to the control session (fold changes ≤
0.67, FDR-adjusted P < 0.0001). Furthermore, mean relative
intensities of these candidates were significantly higher in the CYP2D6
extensive-ultrarapid metabolizer group (n = 37) compared to the poor
metabolizer group (n = 6) (fold changes ≤ 0.67, P < 0.0001).
Conclusion and Implications: The applied untargeted metabolomics
strategy was able to identify five CYP2D6 endogenous metabolites, a
promising discovery for non-invasive phenotyping and personalised
medicine.