Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p‐hydroxylation

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Abstract
Aims Inhibition of cytochrome P450 (CYP) activity by selective serotonin reuptake inhibitors (SSRIs) has frequently been reported with regard to pathways mediated by CYP2D6, CYP3A4/5, and CYP1A2. Little data exist on the capability of SSRIs to inhibit CYP2C9. Methods We investigated the effect of SSRIs on p-hydroxylation of phenytoin (PPH), an established index reaction reflecting CYP2C9 activity, in an in vitro assay using liver tissue from six different human donors. Results In control incubations (without inhibitor), 5-( p-hydroxy-phenyl)-5phenylhydantoin (HPPH) formation rates were: Vmax 0.023 nmol min−1 mg−1; Km 14.3 &mgr;m. Average inhibition constants (Ki ) differed significantly among the SSRIs, with fluvoxamine having the lowest Ki (6 &mgr;m ) followed by R-fluoxetine (13 &mgr;m ), norfluoxetine (17 &mgr;m ), RS-fluoxetine (19 &mgr;m ), sertraline (33 &mgr;m ), paroxetine (35 &mgr;m ), S-fluoxetine (62 &mgr;m ), and desmethylsertraline (66 &mgr;m ). Thus, assuming comparable molar concentrations at the site of inhibition, fluvoxamine can be expected to have the highest probability of interfering with the metabolism of CYP2C9 substrates. S-fluoxetine is on average a 5 fold weaker CYP2C9 inhibitor than either R-fluoxetine or the racemic mixture. Conclusions These findings are consistent with published case reports describing SSRI-related increments in plasma phenytoin levels. Because phenytoin has a narrow therapeutic index, plasma levels should be closely monitored when SSRIs are coadministered.

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