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

Biol Psychiatry. 1999 Sep 15;46(6):839-49. doi: 10.1016/s0006-3223(98)00353-9.

Abstract

Background: Biotransformation of citalopram (CT), a newly available selective 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 microsomes and microsomes from cDNA-transfected human lymphoblastoid cells. Cytochrome inhibition by CT and DCT in liver microsomes was studied using isoform-specific index reactions.

Results: Formation of DCT from CT in liver microsomes had a mean apparent K(m) of 174 mumol/L. Coincubation with 1 mumol/L ketoconazole reduced reaction velocity to 46 to 58% of control values, while omeprazole, 10 mumol/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 velocity, with a possible contribution of 2D6 at therapeutic CT concentrations. CT and DCT themselves produced negligible inhibition of 2C9, 2E1, and 3A, and only weak inhibition of 1A2, 2C19, and 2D6.

Conclusions: Formation of DCT from CT is mediated mainly by P450-3A4 and 2C19, with an additional contribution of 2D6. CT at therapeutic doses in humans may produce a small degree of inhibition of P450-1A2, -2C19, and -2D6, but negligible inhibition of P450-2C9, -2E1, and -3A.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biotransformation / physiology
  • Cell Line, Transformed / drug effects
  • Cells, Cultured
  • Chromatography, High Pressure Liquid / methods
  • Citalopram / analogs & derivatives*
  • Citalopram / pharmacokinetics*
  • Cytochromes / metabolism*
  • DNA, Complementary / drug effects
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / metabolism
  • Serotonin Uptake Inhibitors / pharmacokinetics*
  • Transfection / drug effects

Substances

  • Cytochromes
  • DNA, Complementary
  • Serotonin Uptake Inhibitors
  • Citalopram