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- Title
Citalopram in vitro metabolism in a Beagle dog: A role for CYP2D15 in the production of toxic didesmethylcitalopram?
- Authors
Rochat, Bertrand; Paus, Erik; Maitre, Cedric; Baumann, Pierre
- Abstract
After administration of the serotonergic antidepressant citalopram (CIT) to Beagle dogs, the dogs may experience severe convulsive attacks in relation to the 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 desmethylCIT (DCIT), and of DCIT to DDCIT in the liver microsomes of a single Beagle dog. 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 highaffinity enzyme are between 15 µl/(min × mg of protein) and 52 µl/(min × mg of protein), i.e., very high. In vitro experiments with inhibitors suggest that CYP2D15, which shows an 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, the plasma concentrations of the toxic DDCIT are considerably lower than those observed in dogs, after administration of CIT.
- Subjects
BEAGLE (Dog breed); CYTOCHROME P-450; LIVER microsomes; CITALOPRAM; ISOENZYMES; CYTOCHROME c
- Publication
Veterinární Medicína, 2023, Vol 68, Issue 4, p135
- ISSN
0375-8427
- Publication type
Article
- DOI
10.17221/65/2022-VETMED