Citalopram in vitro metabolism in a beagle dog: A role for CYP2D15 in the production of toxic didesmethylcitalopram?

After administration of the serotonergic antidepressant citalopram (CIT) to beagle dogs, they may experience severe convulsive attacks in relation with considerably higher plasma concentrations of the metabolite didesmethyl-CIT (DDCIT), when compared to those in humans medicated with CIT. This pilot study aimed at determining the role of cytochrome P-450 (CYP450) isozymes in the in vitro metabolism of CIT to desmethyl-CIT (DCIT), and of DCIT to DDCIT in the liver microsomes of a single beagle dog. The incubations with racemic CIT or DCIT reveal a high affinity enzyme with Km between 0.3 µM and 1.4 µM for S- and R-DCIT and S- and R-DDCIT productions, respectively. In comparison to human enzymes, the intrinsic clearance values of this high affinity enzyme are between 15 µL/(min x mg of protein) and 52 µL/(min x mg of protein), i.e. very high. In vitro experiments with inhibitors suggest that CYP2D15, which shows analogy with human CYP2D6, is by far the main CYP450 isozyme involved in the production of DCIT and DDCIT whereas CYP3A12 and CYP2C21/41 showed a weak implication. These observations partly explain why in humans, plasma concentrations of the toxic DDCIT are considerably lower than those observed in dogs, after administration of CIT.