Plasma Concentrations and Cardiovascular Effects of Citalopram Enantiomers After Oral Versus Infusion Citalopram Therapy in Dextromethorphan-Mephenytoin-Phenotyped Patients With Major Depression.

ABSTRACT

BACKGROUND: Authors compared plasma concentrations of citalopram (CIT) enantiomers and their metabolites in patients with depression administered either intravenously (IV) or as oral racemic CIT. Then, plasma concentrations were related to the metabolism of probes used for phenotyping patients with depression for CYP2C19 and CYP2D6 activity and cardiovascular functions. METHODS: Dextromethorphan-mephenytoin-phenotyped patients with depression were administered racemic CIT (days 1 and 2 20 mg/d; days 3-10 40 mg/d) either orally or as a slow-drop infusion for 10 days and were then orally administered the drug for another 32 days. Blood probes were collected at the time of minimal and maximal concentrations on day 10, immediately before and 2 hours after drug administration, and on days 21 and 42. Plasma CIT and its metabolites were assayed by stereoselective high-performance liquid chromatography. RESULTS: The following concentrations (ng/mL) were noted in the group receiving active IV infusion (IV-POS group, n = 27) of racemic CIT on day 10, before drug administration escitalopram (S-CIT) 24 ± 10.2; R-citalopram (R-CIT) 45 ± 14.5; S-desmethyl-CIT 13 ± 4.4; and R-desmethyl-CIT 17 ± 8.2. In patients receiving oral administration (POS-POS group, n = 25), the values were 30 ± 12.7, 51 ± 17.4, 13 ± 4.6, and 17 ± 7.9 ng/mL, respectively. In the IV-POS group, 3 patients were poor dextromethorphan (CYP2D6) metabolizers; in the POS-POS group, one was a poor mephenytoin (CYP2C19) metabolizer. On day 10, before CIT treatment, S/R-CIT and S/R-mephenytoin ratios were significantly correlated, determined at baseline. Overall, CIT reduced the heart rate but did not significantly modify QTc. No relationship was found between any cardiovascular parameters and pharmacokinetic and pharmacogenetic data. CONCLUSIONS: Owing to CIT's high bioavailability, the plasma concentrations of its enantiomers remained largely independent on the administration route. CYP2C19 preferentially demethylated S-CIT after CIT therapy.