title: Influence of quinidine, fluvoxamine, and ketoconazole on the enantioselective pharmacokinetics of citalopram in rats.
abstract: Citalopram (CITA) is available as a racemic mixture or as (+)-(S)-CITA. In humans, CITA is metabolized to demethylcitalopram (DCITA) by CYP2C19, CYP2D6, and CYP3A and to didemethylcitalopram by CYP2D6. There are no data regarding the enzymes involved in CITA and DCITA metabolism in rats. The present study investigated the influence of CYP inhibitors on the enantioselective metabolism of CITA in rats. Male Wistar rats (n = 6) received a single dose of 20 mg x kg-1 CITA after pretreatment with 80 mg x kg-1 quinidine, 10 mg x kg-1 fluvoxamine, 50 mg x kg-1 ketoconazole, or vehicle (control). Blood samples were collected up to 20 h after CITA administration. The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R column. The kinetic disposition of CITA was enantioselective in rats (AUCS/R ratio = 0.4). Coadministration with quinidine resulted in non-enantioselective inhibition of the metabolism of CITA. Coadministration with fluvoxamine or ketoconazole, however, inhibited only the metabolism of (+)-(S)-CITA, but not of (-)-(R)-CITA when the racemic drug was administered to rats.
authors.affiliation: Department of Clinical, Toxicologic and Bromatologic Analyses, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rocha
authors.forename: Eduardo B
authors.initials: EB
authors.lastname: Coelho
authors.forename: Vera L
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D015283:Citalopram / Q000493:pharmacokinetics*; D004347:Drug Interactions; D016666:Fluvoxamine / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D015283:Citalopram; D016666:Fluvoxamine; D007654:Ketoconazole; D011802:Quinidine; D017367:Selective Serotonin Reuptake Inhibitors