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