In vitro assessment of the impact of 30 CYP2C19 variants on citalopram metabolism.

Background: CYP2C19 polymorphisms are correlated with individual variability in response to citalopram treatment. The pharmacogenomic testing of CYP2C19 has been shown to optimize the safety and efficacy of citalopram medication. Exploration of the effect of novel CYP2C19 variants on citalopram could further enhance the potential for personalized citalopram treatment. Objectives: The main goal of this study was to functionally characterize 30 CYP2C19 variants in citalopram metabolism, most of which were rare or novel variants identified in the Chinese Han population. Methods: An in vitro incubation system was set up using recombinant human CYP2C19 variants expressed in Sf21 insect cell microsomes to simulate the citalopram metabolic environment. A high-performance liquid chromatography with fluorescence detection method (HPLC-FLD) was established to quantitatively determine both citalopram and demethylcitalopram. Results: In this study, compared to the wild-type enzyme (CYP2C19*1), 73% (22/30) of the CYP2C19 variants showed significantly different metabolic activities in citalopram metabolism. Among them, two variants, CYP2C19*29 and L16F, showed significantly increased intrinsic clearance (nearly 5-fold and 1.5-fold, respectively). Eighteen variants-CYP2C19*2C, *2F, *2G, *2J, *6, *18, *30, *31, *32, *33, N231T, R124Q, R261W, I327T, A430V, R125G, M255T, and I331V-exhibited significantly decreased intrinsic clearance (18.02-63.16%). Two variants, CYP2C19*3 and 35FS, demonstrated weak or no activity. Moreover, the remaining 27% (8/30) of the CYP2C19 variants showed similar metabolic activities to that of the wild-type enzyme. Conclusion: These CYP2C19 variants require specific attention from physicians and researchers, as their altered metabolic activities may influence the safety and efficacy of citalopram treatment. This work greatly expands the previously underexplored knowledge about the metabolic activities of rare or novel CYP2C19 variants in relation to citalopram medication. These findings may further facilitate the precision use of citalopram in personalized medicine.