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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2018

01-06-2018 | Original Research Article

Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine

Authors: Maxim Kuzin, Georgios Schoretsanitis, Ekkehard Haen, Benedikt Stegmann, Christoph Hiemke, Gerhard Gründer, Michael Paulzen

Published in: Clinical Pharmacokinetics | Issue 6/2018

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Abstract

Background and Objective

An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug–drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs—omeprazole and pantoprazole—and venlafaxine.

Methods

A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40). Plasma concentrations of venlafaxine, O-desmethylvenlafaxine and active moiety (venlafaxine + O-desmethylvenlafaxine), as well as dose-adjusted plasma concentrations, were compared using non-parametrical tests.

Results

Daily doses of venlafaxine did not differ between groups (p = 0.949). The Mann–Whitney U test showed significantly higher plasma concentrations of active moiety, as well as venlafaxine and O-desmethylvenlafaxine, in both PPI groups [p = 0.023, p = 0.011, p = 0.026, +29% active moiety, +27% venlafaxine, +36% O-desmethylvenlafaxine (pantoprazole); p = 0.003, p = 0.039 and p < 0.001, +36% active moiety, +27% venlafaxine, +55% O-desmethylvenlafaxine (omeprazole)]. Significantly higher concentration-by-dose (C/D) values for venlafaxine and active moiety were detected in the pantoprazole group (p = 0.013, p = 0.006, respectively), while in the omeprazole group, C/D ratios for all three parameters—venlafaxine, O-desmethylvenlafaxine and active moiety—were significantly higher (p = 0.021, p < 0.001 and p < 0.001, respectively).

Conclusions

Significantly higher plasma concentrations for all parameters (venlafaxine, O-desmethylvenlafaxine, active moiety) suggest clinically relevant inhibitory effects of both PPIs, most likely on the cytochrome P450 (CYP) 2C19-mediated metabolism of venlafaxine. The findings might be the result of different degrees of CYP2C19 involvement, therefore the inhibition of CYP2C19 by both PPIs may lead to an increased metabolism via CYP2D6 to O-desmethylvenlafaxine.
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Metadata
Title
Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine
Authors
Maxim Kuzin
Georgios Schoretsanitis
Ekkehard Haen
Benedikt Stegmann
Christoph Hiemke
Gerhard Gründer
Michael Paulzen
Publication date
01-06-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0591-8

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