Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation.
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Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, Shader RI
Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation.
Br J Clin Pharmacol. 1997 Nov;44(5):495-8. doi: 10.1046/j.1365-2125.1997.00601.x.
- PubMed ID
- 9384467 [ View in PubMed]
- 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)-5-phenylhydantoin (HPPH) formation rates were: Vmax 0.023 nmol min(-1) mg(-1); Km 14.3 microM. Average inhibition constants (Ki) differed significantly among the SSRIs, with fluvoxamine having the lowest Ki (6 microM) followed by R-fluoxetine (13 microM), norfluoxetine (17 microM), RS-fluoxetine (19 microM), sertraline (33 microM), paroxetine (35 microM), S-fluoxetine (62 microM), and desmethylsertraline (66 microM). 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Fluoxetine Cytochrome P450 1A2 Protein Humans UnknownSubstrateInhibitorDetails Fluoxetine Cytochrome P450 2C9 Protein Humans UnknownSubstrateInhibitorDetails Paroxetine Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Seproxetine Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Sertraline Cytochrome P450 2C9 Protein Humans UnknownSubstrateInhibitorDetails