Metabolism of Citalopram by MAO: Pharmacogenetic and Kinetic Animal Studies

Metabolism of antidepressant drugs occurs mainly in the liver and is controlled by environmental and genetic factors. On the other hand, their metabolism in brain remains unclear, and TDM of their plasma concentrations may not provide accurate information about their presence in brain and on their in situ metabolism.

Citalopram (CIT) is a widely used chiral antidepressant and the most selective serotonin reuptake inhibitor. Its eutomer, S-(+)-CIT, which was recently introduced on the market as escitalopram, is preferentially metabolized by MAO-B in human brain, while the relatively inactive R-(-)-form is mainly metabolized by MAO-A.

The metabolism of CIT and its demethylated metabolites was studied in transgenic mice lacking MAO-A (Tg8). They were generated by infecting with interferon-β (IFN-β) one-cell embryos of C3H/HeJ mice (C3H). Compared to wild type mice, transgenic mice exhibit increased brain levels of serotonin and norepinephrine as well as altered regulations of these neurotransmitter systems.

In order to determine the respective contribution of MAO-A and MAO-B in the metabolism of CIT, we investigated the metabolism of CIT in brain of mice lacking MAO-A compared to wild types.

In C3H mice, MAO-B showed selectivity for the S-(+)-enantiomer (K_m 13µM) and MAO-A for R-(-)-CIT (K_m 140µM). In contrast, in Tg8 mice, MAO-B seemingly counterbalances absence of MAO-A activity (K_m 95µM and K_m 114µM, respectively). These results suggest adaptation of the enzymatic systems to the different genetic context.