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

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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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Acknowledgements

The authors wish to express their gratitude to the significant number of people who contributed with their excellent professional, technical, and pharmacological competence to build up the KONBEST database with 50,049 clinical pharmacological comments as of 2 February 2016 (ranked among the professional groups in historical order): A. Köstlbacher created the KONBEST software in his PhD thesis, based on an idea by E. Haen, C. Greiner, and D. Melchner, along the workflow in the clinical pharmacological laboratory at the Department of Psychiatry and Psychotherapy, University of Regensburg. A. Köstlbacher, along with his colleague A. Haas, continuously maintain the KONBEST software and its data-mining platform (Haas & Köstlbacher GbR, Regensburg, Germany). Laboratory technicians performed the quantitative analysis: D. Melchner, T. Jahner, S. Beck, A. Dörfelt, U. Holzinger, and F. Pfaff-Haimerl. The clinical pharmacological comments regarding drug concentrations were composed by licensed pharmacists and medical doctors. Licensed pharmacists: C. Greiner, W. Bader, R. Köber, A. Hader, R. Brandl, M. Onuoha, N. Ben Omar, K. Schmid, A. Köppl, M. Silva, B. Fay, S. Unholzer, C. Rothammer, S. Böhr, F. Ridders, D. Braun, M. Schwarz, M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, and R. Knorr. Furthermore, the authors thank Mrs. Paraskevi Giannakaki for her expertise in statistics, and Dr. Sarah E. Lammertz for her ability to transfer numbers into intriguing figures.

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Authors and Affiliations

  1. Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Maxim Kuzin, Georgios Schoretsanitis, Gerhard Gründer & Michael Paulzen

  2. JARA, Translational Brain Medicine, Jülich, Germany

    Maxim Kuzin, Georgios Schoretsanitis, Gerhard Gründer & Michael Paulzen

  3. Department of Psychiatry and Psychotherapy, Clinical Pharmacology, University of Regensburg, Regensburg, Germany

    Ekkehard Haen & Benedikt Stegmann

  4. Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany

    Ekkehard Haen & Benedikt Stegmann

  5. University Hospital of Psychiatry, Bern, Switzerland

    Georgios Schoretsanitis

  6. Department of Psychiatry and Psychotherapy, University Medical Center of Mainz, Mainz, Germany

    Christoph Hiemke

  7. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany

    Christoph Hiemke

  8. Alexianer Hospital Aachen, Alexianergraben 33, 52062, Aachen, Germany

    Michael Paulzen

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  1. Maxim Kuzin
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Correspondence to Michael Paulzen.

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Conflict of interests

Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflicts of interest with this publication. Christoph Hiemke has received speaker’s or consultancy fees from Janssen-Cilag and Servier. He is managing director of psiac GmbH, which provides an internet-based DDI program for psychopharmacotherapy. He reports no conflicts of interest with this publication. Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Eli Lilly (Indianapolis, IN, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorf (Aachen, Germany), and has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods GmbH (Selfkant, Germany). He reports no conflicts of interest with this publication. Georgios Schoretsanitis received a grant from the bequest ‘in memory of Maria Zaoussi’, State Scholarships Foundation, Greece, for clinical research in psychiatry for the academic year 2015–2016. Maxim Kuzin, Benedikt Stegmann, Michael Paulzen declare no conflicts of interest.

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Kuzin, M., Schoretsanitis, G., Haen, E. et al. Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine. Clin Pharmacokinet 57, 729–737 (2018). https://doi.org/10.1007/s40262-017-0591-8

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