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.