Does celecoxib inhibit agomelatine metabolism via CYP2C9 or CYP1A2?
Department of Medical Pharmacology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
He et al have reported inhibitory effect of celecoxib on agomelatine metabolism in rat/human liver microsomes, recombinant human cytochrome P450 (CYP) 2C9 in vitro and in Sprague Dawley rats in vivo.1
I would like to emphasize two important points related to celecoxib–agomelatine interaction. Firstly, according to an article cited by He et al written by Liu et al, refers to the metabolism of agomelatine, CYP1A2 and CYP3A4 are the major CYP enzymes but not CYP2C9.2 In that study, Liu et al characterized novel metabolic pathways and CYP-mediated metabolism of agomelatine using metabolomic approaches.2 Among the 39 metabolites of agomelatine determined, 19 have been produced by CYP enzymes, mainly by CYP1A2. He et al cited another review article written by Sansone and Sansone as a reference to the role of CYP2C9 in the metabolism of agomelatine; however, that article also indicated CYP1A2 as the main responsible enzyme for agomelatine metabolism, and nothing was mentioned about the contribution of CYP2C9.3 In earlier in vitro studies and the European Medicines Agency assessment report, CYP1A2, CYP2C9 and CYP2C19 have been suggested as the enzymes responsible for the metabolism of agomelatine. These in vitro data should be carefully interpreted because the type of in vitro drug metabolism system and the concentrations of the drug used in those studies may not directly be correlated with in vivo conditions. For example, in He et al, inhibitory effect of celecoxib was not present at 10 μM and was observed at 50 μM in liver microsomes and this inhibition pattern does not reflect in vivo conditions.1 Therefore, considering the findings in literature, the contribution of CYP2C9 in agomelatine metabolism seems to be minor and needs to be clarified in further studies.
View the original paper by He and colleagues.
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