Liver Injury Induced by the Interaction Between Fluoxetine and Celecoxib: A Case Report and the Literature Review

AUTHORS

Hong-Mei Zhang 1 , Guang-Chen Liu 2 , Yang-Fang He 3 , Wei Zhou 1 , * , Ji-Qiu Hou 4 , **

1 Department of Pharmacy, The First Hospital of Jilin University, Changchun, China

2 Department of Orthopedics, The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China

3 Department of Endocrinology and Metabolism, The Second Hospital of Jilin University, Changchun, China

4 Department of Pharmacy, The Second Hospital of Jilin University, Changchun, China

Corresponding Authors:

How to Cite: Zhang H, Liu G, He Y, Zhou W, Hou J. Liver Injury Induced by the Interaction Between Fluoxetine and Celecoxib: A Case Report and the Literature Review, Iran Red Crescent Med J. 2019 ; 21(9):e93271. doi: 10.5812/ircmj.93271.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 21 (9); e93271
Published Online: September 30, 2019
Article Type: Case Report
Received: May 10, 2019
Revised: August 26, 2019
Accepted: August 26, 2019
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Abstract

Introduction: Fluoxetine is used commonly as an antidepressant and celecoxib is widely used for pain relief and reducing inflammation in various chronic conditions. Both of them can cause liver injury, but it is a rare adverse reaction of their interactions. Here we report a case of liver injury possibly induced by fluoxetine and celecoxib in a female patient.

Case Presentation: A 55-year-old woman who was given fluoxetine for three months and celecoxib for seven days was transferred to the Department of Emergency, the first affiliated hospital of Jilin University, Changchun, China, on March 2019, with icterus on the skin, dark brown urine and pain in the upper abdomen. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) levels were elevated. According to follow-up examination, liver injury and cholecystitis were diagnosed. After discontinuing the two drugs and starting symptomatic treatment, her ALT and AST levels returned to normal.

Conclusions: The mechanism of liver injury induced by fluoxetine and celecoxib remains unclear. Inhibitors and substrates of CYP2D6, CYP2C9, CYP3A4, and CYP2C19 might participate in this situation. The interaction between fluoxetine and celecoxib, as well as other inhibitors and substrates with similar metabolic pathways, are noteworthy.

Keywords

Adverse Drug Reactions Alanine Transaminase Aspartate Aminotransferases CYP2C19 Protein Celecoxib China Fluoxetine Human Injury Liver

Copyright © 2019, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited

1. Introduction

Fluoxetine is a selective inhibitor of neuronal serotonin uptake carrier, it can inhibit the reuptake of serotonin by the serotonin reuptake transporter, thereby enhancing and prolonging the serotonin signaling (1). Fluoxetine is used commonly as an antidepressant but it is also indicated for other psychiatric disorders such as obsessive-compulsive disorder or bulimia nervosa (2). Though fluoxetine is well tolerated by most patients, it still can produce a series of side effects of different degrees, such as neurological problems (dizziness, headache, sleeplessness, depression, thrillingness), digestive system problems (nausea, emesis, diarrhea and constipation), palpitation, leukopenia, sex disorder, bipolar affective disorder, low serum sodium, and organ failure (liver, renal) in rare cases (3, 4).

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) which can selectively inhibit cyclooxygenase-2 (COX-2) and prevent the converting of arachidonic acid to prostaglandin precursors. It is widely used for pain relief and reducing inflammation in various chronic conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (5). Although celecoxib is usually a well-tolerated drug, it is not harmless. It has several side effects such as thrombocytopenia, renal side effects, gastrointestinal bleeding, ulceration, and perforation (6, 7).

Though liver injury induced by fluoxetine (Table 1) or celecoxib (Table 2) has been reported, there are no reports on liver injury caused by their interaction, so this report can be used to warn and guide the clinical use of fluoxetine and celecoxib. Accordingly, we report a case of liver injury caused by both fluoxetine and celecoxib in an adult female.

Table 1. Clinical Characteristics of Fluoxetine-Related Liver Injury
AuthorAge, y/SexCountry/CityDiagnosisClinical CharacteristicsALT, IU/LTherapyPrognosis
Johnston and Wheeler (8)35/MAmerica/AlbuquerqueChronic hepatitisFatigue156DiscontinuedNormal
Agrawal et al. (9)41/FAmerica/ChicagoDILIJaundice1613DiscontinuedNormal
Cai et al. (10)39/MAmerica/MarshfieldAcute hepatitisSharp pain in the right upper quadrant of abdomen, jaundice272DiscontinuedNormal
Cai et al. (10)45/FAmerica/MarshfieldAcute hepatitisSevere pain in the right upper quadrant of abdomen, anorexia, jaundice641DiscontinuedNormal

Abbreviations: DILI, Idiosyncratic drug-induced liver injury; F, female; M, male.

Table 2. Clinical Characteristics of Celecoxib-Related Liver Injury
AuthorAge, y/sexCountry/CityDiagnosisClinical CharacteristicsALT, IU/LTherapyPrognosis
Grieco et al. (11)41/MRome/ItalyCholestatic hepatitisStomach pains, nausea, discomfort, itching, jaundice, dark urine, pale feces234DiscontinuedNormal
Nachimuthu et al. (6)67/FUSA/New YorkAcute hepatocellular and cholestatic liver injurySevere right upper abdominal pain, nausea, vomiting, icterus, and loss of appetite603DiscontinuedNormal
Galan et al. (12)55/FUSA/Royal OakCholestatic hepatitisJaundice, malaise, and pruritic rash261.9DiscontinuedNormal
Alegria et al. (13)49/MPortugal/Carnaxidechronic hepatic diseaseJaundice, fatigue, and choluria49DiscontinuedNormal
El Hajj et al. (14)55/FUnited States /PittsburghDILITired, anorexia, intense itching and dark brown urine258DiscontinuedUnderwent orthotopic liver transplantation
O'Beirne et al. (15)54/FUnited Kingdom /BrightonCholestatic hepatitisPruritus, dark urine232DiscontinuedNormal
Nayudu et al. (16)34/FUSA/BronxDILIEpigastric abdominal pain, nausea458DiscontinuedNormal
Larrey et al. (17)74/FFrance/Nicecholestatic hepatitisAcute jaundice, nausea, asthenic, abdominal pain189DiscontinuedDied

Abbreviations: DILI, Idiosyncratic drug-induced liver injury; F, female; M, male.

2. Case Presentation

A 55-year-old woman was sent to the Department of emergency, the first affiliated hospital of Jilin University, Changchun, China presented with icterus on the skin, dark-brown colored urine and upper abdominal pain in March 2019 (Figure 1). She was recently diagnosed with depression and was prescribed fluoxetine hydrochloride capsules (20 mg per day) by her psychiatrist. She had taken it for 3-months. In addition, the patient had been diagnosed with osteoarthritis for 3-years and took celecoxib capsules when a pain attack. Lately, she got ache of double knee and had celecoxib capsules (200 mg per day) for 7-days. She denied any history of jaundice, alcoholism, smoking or drug use. On the 5th day of celecoxib treatment, reddish urine occurred. Two days later, her urine became dark brown (“coke”) and she complained of severe pain in the upper abdomen. General examination revealed jaundice in the skin and sclera, but without rash. Her blood pressure was 135/85 mmHg and axillary temperature was 36.7ºC. Liver injury and cholecystitis were diagnosed. Laboratory results showed significant damage to the liver (Table 3). Computed tomography (CT) of the abdomen showed gallstones and cholecystitis. The drugs were discontinued due to the alleged liver injury caused by fluoxetine and celecoxib. Symptomatic therapy was given, including hepatoprotection and analgesics. On the 3rd day of the admission, she showed decreased abdominal pain but still had jaundice. On the 7th day after the admission, her jaundice subsided. On the 14th day after the admission, her jaundice was absent and some of her laboratory tests returned to the normal range (Table 3). Then she was discharged.

The patient is doing an examination
Figure 1. The patient is doing an examination
Table 3. Clinical Data of the Patient After the Admission
DateALT, U/LAST, U/LDBIL, μmol/LTBIL, μmol/LGGT, U/LUROBLD
Day 1536.81342.5338.8955.47472.192+1+
Day 6334.75183.4216.226.7353.21+1+
Day 12143355.816.4209--

Abbreviations: ALT, alanine aminotransferase (9 - 50 U/L); AST, aspartate aminotransferase (15 - 40 U/L); DBIL, direct bilirubin (0 - 6.2 μmol/L); TBIL, total bilirubin (3.4 - 17.1 μmol/L); GGT, glutamyl aminopeptidase (10 - 60 U/L); URO, urobilinogen; BLD, urine occult blood.

3. Discussion

To the best of our knowledge, this is the first case of liver injury caused by the interactions of fluoxetine and celecoxib. Our patient did not have viral hepatitis or any other liver diseases. She had taken celecoxib intermittently for 3-years and well-tolerated had taken fluoxetine 3-months with normal liver function and there were no other adverse reactions. When the two drugs were taken together, she developed signs and symptoms of liver injury. Her symptoms and signs were absent within several days after discontinuation of both drugs, and liver function tests went back to the baseline two weeks later. Because of the close association between the application of both drugs and jaundice, we suspected that her liver injury was induced by fluoxetine and celecoxib since we had excluded other factors or drugs that may cause liver injury. On the Naranjo algorithm of adverse drug reaction (ADR) probability, our case scored 6 that indicated a probable ADR (18).

The mechanism of fluoxetine and celecoxib by which caused liver injury remains unclear. There are a few assumptions. First, adverse reactions are caused by host-dependent idiosyncratic reactions or dose-dependent internal reactions. Idiosyncratic reaction is the most common type and is mediated by immune mechanisms or drug metabolism abnormalities (6). Second, fluoxetine and its principal metabolite norfluoxetine (NOR) are strong inhibitors of CYP2D6, and fluoxetine is a strong inhibitor of CYP2C19, whereas NOR is a moderately strong inhibitor of CYP3A4 in vitro and in vivo (19, 20). Some studies supported that CYP2C9 appears to be the principal enzyme mediating fluoxetine N-demethylation (19). Similarly, celecoxib is metabolized by CYP2C9, CYP2D6, and CYP3A4 (21), both experimental data and molecular modeling results clearly support that celecoxib is a substrate of CYP2D6 (7). These two drugs have similar metabolic pathways; it is possible that fluoxetine inhibits the metabolism of celecoxib, leading to an increase in plasma concentrations of celecoxib. The increased concentration of celecoxib may increase the risk of liver injury. Third, according to CYP Allele Nomenclature Database, there are four different distinct phenotypic groups: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers (22). CYP2D6*10, which reduces CYP2D6 activity, is more than 50% frequent in Chinese who are usually intermediate metabolizers (23). This genotype is characterized by its conversion of 188 C to T in exon 1, resulting in the replacement of proline 34 for serine and an unstable and less active enzyme (24). The major CYP2C19 functional alleles associated with a poorly metabolized phenotype are CYP2C19*2 and CYP2C19*3, which the latter is only found in Asian populations. CYP3A4*18 reduces the enzymatic activities and is the most common allele of CYP3A4 gene during Chinese with a frequency of 1% (21). CYP2C9*13 also can significantly decrease CYP2C9 activities but has been found in Chinese with extremely low frequency (25). Maybe this patient has hepatic enzyme deficiency cause higher plasma concentrations and clinical toxicities of therapeutic doses. Forth, the long half-life time of both fluoxetine and NOR, however, can cause pharmacological interactions with celecoxib, since plasma levels can be high even several weeks after discontinuation of the therapy. The inhibitive role may last for a long time after stopping fluoxetine since its long half-life (8 days) and NOR (19.3 days) (26).

In sum, liver injury is still a rare adverse reaction from the interactions of fluoxetine and celecoxib. It is important for clinicians to pay great attention to liver injury resulting from the combination of fluoxetine and celecoxib, or combinations of other inhibitors and substrates of similar metabolic pathways.

Footnotes

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