title: Cytochrome P450-dependent disposition of the enantiomers of citalopram and its metabolites: in vivo studies in Sprague-Dawley and Dark Agouti rats.
abstract: The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n = 9) and DA (n = 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 ± 0.05 vs. 0.80 ± 0.03, P < 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.
authors.affiliation: Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Kingbäck
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.forename: Johan
authors.initials: J
authors.lastname: Ahlner
authors.forename: Finn
authors.initials: F
authors.lastname: Bengtsson
authors.forename: Fredrik C
authors.initials: FC
authors.lastname: Kugelberg
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D015918:Infusion Pumps, Implantable; D008636:Mesencephalon / Q000737:chemistry*; D023421:Models, Animal; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D013045:Species Specificity; D013237:Stereoisomerism
chemical_list: D015283:Citalopram; D019389:Cytochrome P-450 CYP2D6; D017367:Selective Serotonin Reuptake Inhibitors; C514709:demethylcitalopram; C514710:didemethylcitalopram