Citalopram and desmethylcitalopram in vitro: Human cytochromes mediating transformation, and cytochrome inhibitory effects

Background: Biotransformation of citalopram (CT), a newly available selecti ve serotonin reuptake inhibitor antidepressant, to its principal metabolite , desmethycitalopram (DCT), and the capacity of CT and DCT to inhibit human cytochromes P450, were studied in vitro. Methods: Formation of DCT from CT was evaluated using human liver microsome s and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochro me inhibition by CT and DCT in liver microsomes was studied using isoform-s pecific index reactions. Results: Formation of DCT from CT in liver microsomes had a mean apparent K -m of 174 mu mol/L. Coincubation with I mu mol/L ketoconazole reduced react ion velocity to 46 to 58% of control values, while omeprazole, 10 mu mol/L, reduced velocity to 80% of control. Quinidine produced minimal inhibition. DCT was formed from CT by heterologously expressed human P450-2D6, -2C19, -3A4. After accounting for the relative abundance of individual cytochromes , 3A4 and 2C19 were estimated to make major contributions to net reaction v elocity, with a possible contribution of 2D6 at therapeutic CT concentratio ns. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3 A, and only weak inhibition of 1A2 2C19, and 2D6 Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C 19, with an additional contribution of 2D6 CT at therapeutic doses in human s may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6 but negligible inhibition of P450-2C9, -2E1, and -3A. (C) 1999 Society of Biol ogical Psychiatry.