jh
Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access
Article copyright, the authors; Journal compilation copyright, the J Hematol and Elmer PressTM
Journal website http://www.thejh.org
 
Case Report
Volume 2, Number 1, June 2013, pages 37-39
                                                                                

Delayed Elimination of High Dose Methotrexate due to Co-Administration of Omeprazole: A Case Report

Imen Aouintia, b, c, Emna Gaiesa, b, Issam Salouagea, b, Sameh Trabelsia, b, Nadia Jebablia,, Rim Charfia, b, Mohamed Lakhala, b, Anis Klouza, b

aService de Pharmacologie Clinique, Centre National de Pharmacovigilance, Tunis, Tunisia
b
Faculte de Medecine de Tunis, Tunisia
c
Corresponding author: Imen Aouinti, Centre National de Pharmacovigilance, 9, avenue Dr Zouheir Essafi 1006 Tunis, Tunisie 

Manuscript accepted for publication March 12, 2013
Short title: Methotrexate and Omeprazole Interaction

doi: http://dx.doi.org/10.4021/jh71w


Abstract

 

Methotrexate High Doses (HD-MTX) is indicated for the treatment of cancer diseases and its use requires strict precautions to prevent toxic side effects. It has also numerous drug interactions, the most known are interaction with trimethoprim - sulfamethoxazole (TMP-SMX) and Non Steroidal Anti-Inflammatory drugs (NSAIDs), which can exacerbate toxicity of MTX. We report herein a case of delayed elimination of HD-MTX due to co-administraion of omeprazole. B.A, a 17-year-old female having acute lymphoblastic leukemia (ALL). She is treated since September 2011 by HD-MTX every month for 6 months. The elimination of MTX was usually averaged at H72. Because of epigastralgia, the sixth cycle of HD-MTX was associated this time to omeprazole 20 mg/d during the entire cycle. MTX monitoring showed a high concentration at H36 (23 µmol/L) and a delayed elimination. In fact, MTX remained above 0.2 µmol/L until H164. The patients serum creatinin was normal but the liver function was altered marked by transaminases increase observed at H48 (AST = 2N, ALT = 5N). Delayed elimination of MTX was not observed in every patient receiving PPIs and the reason remains unclear. Mechanisms may include the H+/K+ ATPase pump. It seems also that inhibition of renal transporters of MTX is involved in this interaction. Genetic factors may be associated with an accentuated risk of toxicity. Because of the severity of this type of drug interaction and the frequent ambulatory use of PPIs, it is important to mention such drug-drug interaction and to find an alternative for omeprazole during HD-MTX cycles.

Keywords: Methotrexate; Omeprazole; Drug interaction; Hepatotoxicity


Introduction
 

Methotrexate (MTX) is a folic acid analog. Since its discovery in 1948, the clinical applications of MTX have widened; and in order to overcome resistances, the concept of MTX High-Doses (HD-MTX > 500 mg/m2) has been proposed. HD-MTX is indicated for the treatment of cancer diseases as lymphoma, osteosarcoma and acute leukemia. Its use requires strict precautions (Alkaline hydration, folinic acid rescue, plasma concentration monitoring, early management of toxicities) to prevent toxic side effects [1, 2]. On the other hand, MTX is subject to numerous drug interactions, the most known are interaction with trimethoprim - sulfamethoxazole (TMP-SMX) and non Steroidal Anti-inflammatory Drugs (NSAIDs), which can exacerbate its toxicity. Drug interaction between MTX and proton pump inhibitors (PPIs) is rarely reported and its physiopathology remains still discussed [3]. 

We report herein a case of delayed elimination of HD-MTX due to co-administration of omeprazole assessed in Service of Clinical Pharmacology of Tunis.


Case Report
 

B.A, a 17-year-old female with no medical history has an Acute Lymphoblastic Leukemia (ALL). The disease was revealed by meningeal involvement manifested as facial paralysis. 

She is treated since September 2011 by HD-MTX (5 g/m2/24 h) every month for 6 months. The response to the treatment was favorable marked by a remission and the tolerance was good with absence of side effects. Throughout these cycles, MTX elimination was usually averaged at H72 (0.40 ± 0.37 µmol/L) and H36 was average 1.97 ± 1.77 µmol/L (Fig. 1). These cycles were not associated with omeprazole.

 

Figure 1. MTX plasmatic concentration during the five last cycles.


The sixth cycle of HD-MTX started in 16/03/12. Because of epigastralgia, it was associated this time to omeprazole 20 mg per day during the entire cycle. The monitoring of MTX plasma levels showed a high MTX concentration at H36 (23 µmol/L) and a delayed elimination. In fact, MTX concentration remained above 0.2 µmol/L until H164 (
Fig
. 1). 

The patients serum creatinin was normal but the liver function was altered marked by transaminases increase observed at H48 (AST = 2N, ALT = 5N). 

The outcome was favorable with a decrease of transaminases level after the end of MTX cycle. 

In April 2012, the patient underwent another cycle of HD-MTX. This time, it was not associated with omeprazole. The concentration of MTX at H36 was 0.87 µmol/L below the toxic level and it was eliminated on 72 hours (Fig. 1). 
 

Discussion 

The use of HD-MTX necessarily needs a Therapeutic Drug Monitoring (TDM). In fact, it is subject to large inter and intra-individual variations of its pharmacokinetics. Its elimination could be prolonged in patients with renal impairment or third space fluid collections, due to a slow redistribution from these extravascular fluid accumulations [1].

A delayed elimination of MTX is a cause of toxic effects as mucositis, renal and hepatic impairment, hematological and neurological toxicity [2, 4].

Drug interactions may also lead to a delayed elimination of MTX. The most described one are NSAIDs. Interaction with NSAIDs results from four mechanisms: a competition for renal tubular secretion via organic anion transporter 3 (OAT3), a removal from the binding site to serum protein, a reduction in hepatic metabolism and a reduction in glomerular filtration through decreasing prostaglandin synthesis [5, 6]. There are also interactions with other drugs like SMX-TMP, probenecid or penicillin G through inhibiting renal clearance of MTX [7, 8].

Less frequently, an interaction between MTX and omeprazole was suggested. A review in 2012 [3] concluded that there is evidence to suggest that concomitant use of MTX (primarily at high doses) with PPIs may decrease MTX clearance, leading to elevated MTX serum levels and/or its metabolite hydroxymethotrexate, possibly leading to MTX toxicities.

Our case report showed a clear interaction between MTX and PPIs. This fact was deduced by the delayed elimination of MTX when associated with PPIs at the sixth cycle and by the absence of other risk factors (a normal renal function, no third space fluid, no other potential drug interaction). Moreover, no delayed elimination was noticed in cycles without PPIs. This interaction results in toxic MTX concentration (H36 = 23 µmol/L) with a delayed elimination and therefore a perturbation of liver function.

MTX is renally eliminated by glomerular filtration and active tubular secretion through a hydrogen-ion-dependent mechanism [9]. This phenomenon occurs in proximal tubular cells.

Mechanisms of the MTX delayed elimination in this case of drug interaction may include the renal hydrogen/potassium adenosine triphosphate pump (H+/K+ ATPase) which can be blocked by PPIs [9, 10]. Besides, PPIs showed also in vitro inhibition of MTX transport via BCRP (Breast Cancer Resistance Protein) [10]. In fact, MTX elimination involves Organic Anion Transporter 3 (OAT3), Multidrug Resistance-associated Protein (MRP) and BCRP [1, 11]. Therefore, the interaction between MTX and PPIs cannot be explained solely by the inhibitory effects of PPIs on renal BCRP.

This interaction is controversial. In fact, delayed elimination of MTX was not observed in every patient receiving PPIs and the reason remains unclear. Polymorphism of CYP2C19, a principal enzyme involved in the metabolism of PPIs and polymorphism of BCRP can be considered a potential explanation [1]. Thus, genetic factors may be associated with an accentuated risk of toxicity [1, 10].

Conclusion 

More investigations are necessary to elucidate the mechanism of interaction between PPIs and MTX. At this state of knowledge and because of the severity of this type of drug interaction and the frequent ambulatory use of PPIs, it is important to mention such drug-drug interaction and to find an alternative for omeprazole during HD-MTX cycles. 
 

 
 
References
 

1.

Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, et al. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009;67(1):44-49.
doi
pubmed

2.

Gaies E, Jebabli N, Trabelsi S, Salouage I, Charfi R, Lakhal M, Klouz A. Methotrexate Side Effects: Review Article. J Drug Metab Toxicol 2012; 3: 123-125.

3.

Bezabeh S, Mackey AC, Kluetz P, Jappar D, Korvick J. Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist. 2012;17(4):550-554.
doi
pubmed

4.

Richard MA, Guillaume JC. Methotrexate. Ann Dermatol Venerol 2007; 34: 923-926.
doi

5.

Bagatini F, Blatt CR, Maliska G, Trespash GV, Pereira IA, Zimmermann AF, Storb BH, et al. Potential drug interactions in patients with rheumatoid arthritis. Rev Bras Reumatol. 2011;51(1):20-39.

6.

Maeda A, Tsuruoka S, Kanai Y, Endou H, Saito K, Miyamoto E, Fujimura A. Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells. Eur J Pharmacol. 2008;596(1-3):166-172.
doi
pubmed

7.

Haidar C, Jeha S. Drug interactions in childhood cancer. Lancet Oncol. 2011;12(1):92-99.
doi

8.

Beijnen JH, Schellens JH. Drug interactions in oncology. Lancet Oncol. 2004;5(8):489-496.
doi

9.

Beorlegui B, Aldaz A, Ortega A, Aquerreta I, Sierrasesumega L, Giraldez J. Potential interaction between methotrexate and omeprazole. Ann Pharmacother. 2000;34(9):1024-1027.
doi
pubmed

10.

Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, et al. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004;64(16):5804-5811.
doi
pubmed

11.

Leveque D, Lemachatti J, Nivoix Y, Coliat P, Santucci R, Ubeaud-Sequier G, Beretz L, et al. [Mechanisms of pharmacokinetic drug-drug interactions]. Rev Med Interne. 2010;31(2):170-179.
doi
pubmed

 


This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Digital Object Identifier (DOI): http://dx.doi.org/10.4021/jh71w
About DOI and CrossRef
Journal of Hematology is published by Elmer Press Inc.

 
Home     |     Log In     |      About     |      Search     |      Current     |      Archives     |      Submit      |     Subscribe


 

     

Aims and Scope

Current Issues

Conflict of Interest

About Publisher

Editorial Board

Archives

Copyright

Company Profile

Editorial Office

Misconduct and Retraction

Permissions

Company Registration

Contact Us

Abstracting and Indexing

ICMJE

Ownership

Instructions to Authors

Access

Declaration of Helsinki

Contact Publisher

Submission Checklist

Reprints

Terms of Use

Company Address

Submit a Manuscript

Open Access Policy

Privacy Policy

Browse Journals

Publishing Fee

Publishing Policy

Disclaimer

Recent Highlights

Peer-Review Process

Publishing Quality

Code of Ethics

Advertising Policy

Manuscript Tracking

Advanced Search

For Librarians

Careers

Publishing Process

Publication Frequency

For Reviewers

Propose a New Journal

       
       

Journal of Hematology, quarterly, ISSN 1927-1212 (print), 1927-1220 (online), published by Elmer Press Inc.            
The content of this site is intended for health care professionals.
This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC BY-NC 4.0)



This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.thejh.org    editorial contact: editor@thejh.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada
 

© Elmer Press Inc. All Rights Reserved.

IMPORTANT: THIS JOURNAL SITE OUTLOOK IS DESIGNED BY THE PUBLISHER AND COPYRIGHT PROTECTED. DO NOT COPY!