Sertraline, enzyme inhibition

The major distinguishing characteristic among the SSRIs is CYP enzyme inhibition. Fluvoxamine, fluoxetine, and paroxetine produce substantial inhibition of one or more CYP enzymes, whereas citalopram and sertraline do not (Table 7-29). In fact, fluvoxamine, fluoxetine, and paroxetine have all caused fatal drug-drug interactions via such CYP enzyme inhibition (339, 496, 497). 

Liston HL, DeVane CL, Boulton DW, et al. Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. J Clin Psychopharmacol 2002 22 169-173. 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

Selective serotonin reuptake inhibitors (SSRIs) [P] Fluoxetine and paroxetine inhibit CYP2D6 and decrease metabolism of antidepressants metabolized by this enzyme (eg, desipramine). Citalopram, sertraline, and fluvoxamine are only weak inhibitors of CYP2D6, but fluvoxamine inhibits CYP1A2 and CYP3A4 and thus can inhibit the metabolism of antidepressants metabolized by these enzymes. 

Another important CYP450 enzyme for antidepressants is 2D6. Tricyclic antidepressants are substrates for 2D6, which hydroxylates and thereby inactivates them (Fig. 6—14). Several antidepressants from the SSRI class are inhibitors of CYP2D6 (Fig. 6—15). There is a wide range of potency for 2D6 inhibition by the five SSRIs, with paroxetine and fluoxetine the most potent and fluvoxamine, sertraline, and citalopram the least potent. 

CYP2D6 biosensor for antidepressants (sertraline and fluxetine). Previous studies on PANI- and polythiophene-based CYP-biosensors for fluoxetine showed that the uncompetitive inhibition kinetics between the CYP enzyme and fluoxetine is based on the mono-oxygenation reaction of the enzyme [13], The response of the Au PANSA/CYP2D6... 

Sertraline, at its usual effective dose of 50 mg/day, has been found to cause less pronounced modifications in plasma concentrations of tricyclic antidepressants (TCAs) as compared with other selective serotonin reuptake inhibitors (SSRIs) (mainly studies with fluoxetine, fluvoxamine, and paroxetine). However, since inhibition of the hepatic enzyme CYP2D6 is dose-dependent, significant increase in plasma concentration of TCAs may occur when higher doses of sertraline are administered. Acute liver damage possibly related to sertraline and venlafaxine ingestion has been reported. 

An in vitro investigation found that fluoxetine and fluvoxamine inhibited the metabolism of phenytoin by the cytochrome P450 isoenzyme CYP2C9 in human liver tissue. This would presumably lead to a rise in serum phenytoin levels. In this study, sertraline was a weaker inhibitor of CYP2C9, and was considered less likely to interact with phenytoin.A similar study also suggested that the risk of interaction was greatest for fluoxetine, and less likely with sertraline and paroxetine. Sertraline plasma levels may be reduced because of enzyme induction by phenytoin which would increase its metabolism and clearance from the body. ... 

A case has also been reported of a patient with schizophrenia and depression, whose cognitive symptoms improved when he took clozapine and fluoxetine, but when treatment was changed to sertraline, this improvement was not sustained. The authors tentatively suggested that the fluoxetine elevated plasma clozapine levels by inhibition of CYP2D6, whereas this effect was not seen with sertraline as it is a much weaker inhibitor of this enzyme. However, this explanation has been questioned, since the role of other drug metabolising enzymes was not considered. ... 

In vitro studies with human liver microsomes have shown that fluvoxam-ine inhibits the eytoehrome P450 isoenzyme CYP1A2, the principal enzyme responsible for the metabolism of theophylline. This results in raised theophylline levels and toxieity. This metabolic function, and hence interaction, appears to be severely reduced in patients with severe cirrhosis, probably due to redueed hepatie expression of CYP1A2 and reduced uptake of fluvoxamine. The other SSBIs, citalopram, fluoxetine, paroxetine and sertraline only weakly inhibited CYP1A2 in vitro, and consequently would not be expeeted to interact. ... 

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