Stereoselective single‐dose kinetics of citalopram and its metabolites in rats

Abstract

The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5-10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats.

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

“…The total loss of P-gp might change the volume of distribution which can influence the drug elimination (Endres et al, 2006). These enantiomeric ratios are much higher compared to corresponding ratios in humans and rats (S/R ratios of 0.59 in patients and around 0.9 in rats given 10 mg/kg citalopram) indicating possible species differences Kugelberg et al, 2001Kugelberg et al, , 2003. When comparing S/R ratios, there can be a stereoselective metabolism in mice not seen in humans or the opposite situation.…”

Lasting Syndrome of Depression Produced by Reduction in Serotonin Uptake during Postnatal Development: Evidence from Sleep, Stress, and Behavior

“…This is similar to data observed after a neonatal treatment with other SSRIs (Hansen et al, 1997;Maciag et al, 2006a,b). Interestingly, the rapidly metabolized citalopram was less efficient than slowly metabolized fluoxetine (Geczy et al, 2000;Kugelberg et al, 2003;Ansorge et al, 2008) to induce deficits in novelty-induced tests of behavioral inhibition (which are sensitive to mild increases in anxiety) (Ansorge et al 2008). This suggests that a stronger or sustained increase in brain serotonin compared with that induced by escitalopram may be required to produce anxiety (see also Gross et al, 2002).…”

Enantioselective analysis of citalopram and demethylcitalopram in human and rat plasma by chiral LC‐MS/MS: Application to pharmacokinetics

“…7 Kugelberg et al 8 reported S/R plasma concentration ratios of 0.94, 0.83, and 0.34 for CITA and of 0.85, 0.37, and 0.36 for DCITA in rats treated with multiple doses of 10, 20, and 100 mg CITA/kg/day for 10 days, respectively, suggesting that a dose increase reduces the S/R ratio of CITA and DCITA. Kugelberg et al 9 demonstrated enantioselectivity in the metabolism of CITA in rats receiving subcutaneous administration of a single dose of 20 or 100 mg/kg. The authors reported S/R plasma concentration ratios of 0.7 and 0.6 for CITA 10 and 20 h after administration of the racemic drug, respectively.…”

“…In the two studies, CITA was administered with an osmotic pump, i.e., the absorption process was devoid of presystemic elimination. Kugelberg et al 9 observed enantioselectivity in the metabolism of CITA in rats subcutaneously injected with a single dose of 20 or 100 mg/kg. The authors reported S/R plasma concentration ratios of 0.6 for CITA, 20 h after administration of the drug.…”