Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram).

There is limited documentation of the importance of heterozygous cytochrome P450 (CYP) mutations on drug exposure. This study was designed to evaluate the influence of heterozygous mutations in CYP2C19 on the serum concentration of racemic citalopram and escitalopram (S-citalopram). Eighty-three samples from subjects with determined CYP2C19 and CYP2D6 genotype receiving racemic citalopram or S-citalopram as part of their clinical treatment were collected from a routine therapeutic drug monitoring database. Concentration/dose (C/D) ratios, parent drug/metabolite ratios, and serum concentrations in CYP2C19 homozygous extensive metabolizers (EMs) and heterozygous extensive metabolizers (HEMs) were compared. The median C/D ratio was significantly higher in the HEM group compared with the EM group, both for racemic citalopram (8.0 vs. 4.9, P < 0.01) and S-citalopram (5.3 vs. 2.6, P < 0.01). The median parent drug/metabolite ratio was significantly higher in the HEM group compared with the EM group, both for racemic citalopram (2.9 vs. 1.6, P < 0.01) and for S-citalopram (2.4 vs. 1.2, P < 0.01). A higher median non-dose-corrected serum concentration also was observed in HEMs compared with EMs both for S-citalopram (P < 0.01) and racemic citalopram (P = 0.066). This study shows that the metabolism of racemic citalopram and S-citalopram is significantly impaired in CYP2C19 HEMs. Higher absolute serum concentrations indicate that this is not compensated for by dose reductions in clinical practice.