Pharmacokinetic and pharmacodynamic responses to chronic administration ofthe selective serotonin reuptake inhibitor citalopram in rats

The number of drugs used to treat affective disorders such as depression is rapidly increasing. Citalopram (CIT), an antidepressant, is a selective se rotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In the prese nt study, rats were treated with 10 mg/kg/d racemic CIT for two weeks with use of osmotic pumps, and the following were monitored: open-field behavior , racemic and enantioselective concentrations of CIT and metabolites in blo od, brain parenchyma, and extracellular space, and the brain extracellular monoamine levels. The racemic CIT concentration in serum was estimated abou t tenfold lower than in brain parenchyma but much higher than in brain extr acellular fluid. The major CIT metabolites, demethylcitalopram (DCIT) and d idemethylcitalopram (DDCIT) were 20% and 30%, respectively, of the amounts of CIT in serum and even lower in the brain parenchyma. The S-enantiomer/R- enantiomer ratios for CIT and DCIT were about 1.01 and 0.31, respectively, in blood and brain. There was a clear correlation between the different dru g components within and between blood and brain compartments. Citalopram ha d no measured effect on open-field behavior, but it elevated extracellular 5-HT and decreased 5-HIAA levels. No correlations between any of the drug c omponents and the brain monoamines were found. In summary, the drug compone nts after chronic dosing correlated well between the periphery and the brai n, but not with the brain monoamine concentrations. Further studies investi gating the combined pharmacokinetic/dynamic effects could take advantage of blood drug monitoring for the commonly used novel antidepressant drugs.