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Vol. 31, Issue 3, 289-293, March 2003
Department of Pharmacology and Experimental Therapeutics,
Tufts University School of Medicine (K.M.B., L.L.vM., D.J.G.), and the
Division of Clinical Pharmacology, Tufts-New England Medical Center
(L.L.vM., D.J.G.), Boston, Massachusetts; and Pfizer Inc., Groton,
Connecticut (K.V., R.S.O.)
Paroxetine, a selective serotonin reuptake inhibitor, is a potent
inhibitor of cytochrome P450 2D6 (CYP2D6) 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. The kinetic parameters of inhibition
were also estimated by varying the time of preincubation as well as the
concentration of inhibitor. From these data, a Kitz-Wilson plot was
constructed, allowing the estimation of both an apparent inactivator
concentration required for half-maximal inactivation
(KI) and the maximal rate constant of
inactivation (kINACT) value for this
interaction. Preincubation of paroxetine with human liver microsomes
caused an approximately 8-fold reduction in the IC50 value
(0.34 versus 2.54 µM). Time-dependent inhibition was demonstrated
with an apparent KI of 4.85 µM and an
apparent kINACT value of 0.17 min
1. 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. In contrast,
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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