The effects of selective serotonin reuptake inhibitors and their metabolites on S‐mephenytoin 4'‐hydroxylase activity in human liver microsomes.

Abstract

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 gIM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

(+)-N-3-Benzyl-Nirvanol and (−)-N-3-Benzyl-Phenobarbital: New Potent and Selective in Vitro Inhibitors of CYP2C19

“…Omeprazole and tranylcypromine, with K i values of 4.1 and 8.7 M, respectively (VandenBranden et al, 1996;Wienkers et al, 1996), have occasionally been used as CYP2C19 inhibitors, but both compounds also inhibit CYP3A4 and CYP2A6 with K i values of 79 and 0.04 M, respectively (Lampen et al, 1995;Draper et al, 1997), and therefore do not demonstrate high selectivity. The most potent inhibitors for CYP2C19 found to date are probably norfluoxetine and ticlopidine with K i values of 1.1 and 1.2 M, respectively (Kobayashi et al, 1995;Ko et al, 2000). However, both drugs are also potent inhibitors of CYP2D6 (Stevens and Wrighton, 1993;Ko et al, 2000).…”

Synthesis, characterization and pharmacological evaluation of mixed ligand-metal complexes containing omeprazole and 8-hydroxyquinoline

“…Thus, these SEM results confirmed the nano-structured behavior of the synthesized metal complexes. H NMR spectra of the synthesized mixed ligand complexes was obtained in deuterated DMSO-d 6 . In 1 H NMR spectrum, the signal that appeared around the δ 3.42-3.51 ppm was assigned to O-CH 3 , while methylene (-CH 2) protons were responsible for the doublet peak at δ 4.64-4.69 ppm in all the synthesized complexes.…”

“…The plasma elimination half-life (t 1/2β ) of omeprazole is usually shorter than one hour, although a few individuals exhibit slower elimination (t 1/2β ≈ 2h). These individuals have recently been shown to be poor hydroxylators of S-mephenytoin, which suggests that a major part of omeprazole metabolism is mediated by S-mephenytoin hydroxylase, an enzyme within the cytochrome P450 system [5,6].…”

Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine

“…Fluoxetine also undergoes CYP2C19-mediated O-dealkylation to the p-trifluoromethylphenol metabolite (Liu et al, 2002). In addition, racemic fluoxetine and/or its enantiomers have been shown to be reversible inhibitors of CYP2D6 (Brosen and Skjelbo, 1991;Stevens and Wrighton, 1993), CYP2C19 (Kobayashi et al, 1995;Foti and Wahlstrom, 2008), CYP3A4 (von Moltke et al, 1994;Ring et al, 1995), and CYP2C9 (Schmider et al, 1997;Hemeryck et al, 1999). Fewer studies have been conducted examining the potential for fluoxetine to be a mechanism-based inhibitor of P450.…”