OXIDATIVE STRESS-BASED HEPATOTOXICITY OF DULOXETINE IN WISTAR RATS

Akanksha Mishra; Amit K. Keshari; Ashok K. Singh; Siddhartha Maity; Bankim Nandy; Sudipta Saha

doi:10.22159/ijpps.2016v8i11.8857

Authors

Akanksha Mishra Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareli Road, Lucknow 226025, India
Amit K. Keshari Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareli Road, Lucknow 226025, India
Ashok K. Singh Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareli Road, Lucknow 226025, India
Siddhartha Maity Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
Bankim Nandy Department of Pharmaceutical Sciences, Joyti Vidyapeeth Womenâ€™s University, Jaipur, Rajasthan
Sudipta Saha Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rai Bareli Road, Lucknow 226025, India

DOI:

https://doi.org/10.22159/ijpps.2016v8i11.8857

Keywords:

Duloxetine, CYP1A2 enzyme, Hepatotoxicity, Oxidative stress

Abstract

Objective: Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor used in major depressive disorders, urinary incontinence and diabetic peripheral neuropathic pain. It is reported to be associated with several types of liver injuries, including hepatocellular, cholestatic and mixed hepatocellular-cholestatic patterns. The objective of this study was to assess the effect of duloxetine or its metabolites on oxidative stress-induced liver damages.

Methods: In this study, animals were divided into five groups. In the first group, the only vehicle was given orally for 21 d. The second group has been considered as hepatotoxic control group where Erythromycin was given orally for 14 d and remaining three groups have been considered as test groups where duloxetine, fluvoxamine and duloxetine along with fluvoxamine were administered orally for 21 d. Liver GSH, oxidised lipid (malonaldehyde MDA), superoxide dismutase (SOD), catalase (CAT), protein carbonyl (PC) and plasma alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) levels were measured to determine the level of hepatotoxicity. Scanning electron microscopy (SEM) study of liver tissues was also performed to examine the liver injuries.

Results: GSH and SOD levels were found to be decreased in duloxetine-treated groups with respect to the hepatotoxic control group, whereas increased level of MDA, CAT and PC signify the damages of liver cells. Increased level of plasma ALT, AST and ALP at the same time indicated liver tissue damage. Opposite effects were observed in the case of duloxetine and fluvoxamine-treated groups. SEM of liver tissues revealed that the tissue injury occurred in Duloxetin treated groups, whereas the restoration of normal tissue architecture took place due to the administration of duloxetine and fluvoxamine-treated groups.

Conclusion: Our results collectively indicated that hydroxylated and epoxide metabolites of duloxetine might have hepatotoxic potential due to oxidative stress produced by the release of free radicals or reactive oxygen species.

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