ORIGINAL RESEARCH ARTICLE
Effects of the Proton Pump Inhibitors Omeprazole
and Pantoprazole on the Cytochrome P450-Mediated Metabolism
of Venlafaxine
Maxim Kuzin
1,2
•
Georgios Schoretsanitis
1,2,5
•
Ekkehard Haen
3,4
•
Benedikt Stegmann
3,4
•
Christoph Hiemke
6,7
•
Gerhard Gru
¨
nder
1,2
•
Michael Paulzen
1,2,8
Published online: 2 September 2017
Ó Springer International Publishing AG 2017
Abstract
Background and Objective An increasing trend in pre-
scribing proton pump inhibitors (PPIs) inevitably increases
the risk of unwanted drug–drug interactions (DDIs). The
aim of this study was to uncover pharmacokinetic inter-
actions between two PPIs—omeprazole and pantopra-
zole—and venlafaxine.
Methods A therapeutic drug monitoring database con-
tained 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 sig-
nificantly 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-desmethylven-
lafaxine (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.
1 Introduction
Multimorbidity inevitably leads to polypharmacy,
enhancing the risk of drug-related risks [1, 2]. The potential
for drug–drug interactions (DDIs), which are associated
& Michael Paulzen
m.paulzen@alexianer.de
1
Department of Psychiatry, Psychotherapy and
Psychosomatics, RWTH Aachen University, Pauwelsstr. 30,
52074 Aachen, Germany
2
JARA, Translational Brain Medicine, Ju
¨
lich, Germany
3
Department of Psychiatry and Psychotherapy, Clinical
Pharmacology, University of Regensburg, Regensburg,
Germany
4
Department of Pharmacology and Toxicology, University of
Regensburg, Regensburg, Germany
5
University Hospital of Psychiatry, Bern, Switzerland
6
Department of Psychiatry and Psychotherapy, University
Medical Center of Mainz, Mainz, Germany
7
Institute of Clinical Chemistry and Laboratory Medicine,
University Medical Center of Mainz, Mainz, Germany
8
Alexianer Hospital Aachen, Alexianergraben 33, 52062
Aachen, Germany
Clin Pharmacokinet (2018) 57:729–737
https://doi.org/10.1007/s40262-017-0591-8
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