Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 activity, but the mechanism of inhibition is not established

Kirk M. Bertelsen; Karthik Venkatakrishnan; Lisa L. von Moltke; R. Scott Obach; David J. Greenblatt

2003

Scholarcy highlights

  • Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 activity, but the mechanism of inhibition is not established
  • To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine
  • A Kitz-Wilson plot was constructed, allowing the estimation of both an apparent inactivator concentration required for half-maximal inactivation and the maximal rate constant of inactivation value for this interaction
  • Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex
  • This pattern is consistent with the metabolism of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P450 enzymes
  • Quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine
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