In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats

Abstract

The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted. By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed. In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg(-1) day(-1) were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions. In the group treated with 100 mg kg(-1) day(-1), the serum and brain total CIT levels were found to be 20 times and 6 - 8 times higher than in the rats treated with 10 or 20 mg kg(-1) day(-1), respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum. In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed. In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

Figure 1

Plot of the concentrations of the total sum of the S- plus R-enantiomers of citalopram (CIT) obtained for serum versus brain in rats treated with (a) 10 mg kg⁻¹ day⁻¹ (CIT-10); (b) 20 mg kg⁻¹ day⁻¹ (CIT-20); and (c) 100 mg kg⁻¹ day⁻¹ (CIT-100) for 10 days. Closed boxes denote serum versus cortex (Ctx) and open boxes denote serum versus mesencephalon-pons (Mes). (r=coefficient of correlation).

Figure 2

Plot of the correlation between the serum concentrations of the total sum of the S- plus R-enantiomers of citalopram (CIT) and the S/R ratios of CIT in rats treated with 10 mg kg⁻¹ day⁻¹ (CIT-10), 20 mg kg⁻¹ day⁻¹ (CIT-20), and 100 mg kg⁻¹ day⁻¹ (CIT-100) for 10 days. (r=coefficient of correlation).

Figure 3

Plot of the correlation between the serum concentrations of the total sum of the S- plus R-enantiomers of citalopram (CIT) and the open-field locomotor activity during 60 min at daytime of rats treated with 10 mg kg⁻¹ day⁻¹ (CIT-10), 20 mg kg⁻¹ day⁻¹ (CIT-20), and 100 mg kg⁻¹ day⁻¹ (CIT-100) for 10 days. (r=coefficient of correlation).