Pharmacokinetic and Behavioural Effects of Antidepressants Given Orally via Drinking Water in Rats

Citalopram, a selective Serotonin Reuptake Inhibitor (SSRI), is used for treatment of depressive disorders. In man, citalopram is administered orally and therapeutic concentrations are established. However, little is known about the various clinical effects occurring in relation to the corresponding therapeutic concentrations. Therefore an animal model of depression was developed in rats by using psychosocial stress with therapeutic drug monitoring to further evaluate this question. The half-life of citalopram, however, is different in human and rodents. Rats metabolize the drug 5 to 10 times faster than humans. Therefore a citalopram monitoring study was done.

Methods: Citalopram was administered orally to rats via drinking water in doses of 10, 20 and 40mg/kg for 5 days. On day five, a jugular vein catheter was implanted and blood was collected for drug monitoring for 15 hrs in 3 hrs intervals and the amount of consumed drug solution was measured. The dose was adjusted to individual water consumption of each animal. Behavioral effects of were studied in psychosocially stressed animals without and with citalopram treatement.

Results: At the dose 40mg/kg the drug was detectable during the entire sampling period. Mean ratios of concentrations citalopram to N-desmethylcitalopram were 1:3. At the dose 20mg/kg citalopram was detectable for 6 hrs and its metabolites during the whole sampling period. At dose 10mg/kg the parent drug was not detectable in blood. Its metabolite was detectable for 12 hrs after the last drug intake. Under the low dose, drug effects were observed for motor behaviour.

Our results indicate that the oral application of a new antidepressant like citalopram is possible in an animal models of depression, even at high doses that were necessary to attain blood levels that are comparable to those observed in patients treated with therapeutic doses of the drug.