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 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 »  References
 »  Article Figures
 »  Article Tables

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RESEARCH ARTICLE
Year : 2013  |  Volume : 45  |  Issue : 2  |  Page : 121-125
 

Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals


Department of Pharmacology, NGSM Institute of Pharmaceutical Sciences, Deralakatte, Mangalore, Karnataka, India

Date of Submission13-Feb-2012
Date of Decision14-May-2012
Date of Acceptance08-Jan-2013
Date of Web Publication11-Mar-2013

Correspondence Address:
Chakrakodi S Shastry
Department of Pharmacology, NGSM Institute of Pharmaceutical Sciences, Deralakatte, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.108280

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 » Abstract 

Objectives: Aripiprazole, a new atypical antipsychotic drug extensively metabolized by enzyme CYP3A4, is found to produce asymptomatic elevation of serum transaminase levels on long-term treatment. The present study aims to evaluate the hepatotoxic effect of aripiprazole when coprescribed with carbamazepine and fluvoxamine.
Materials and Methods: The rats were subjected to chronic treatment with two different doses, therapeutic dose (TD) and maximum therapeutic dose (MTD), of aripiprazole in combination with carbamazepine and fluvoxamine. The changes in hepatic function was assessed by various biochemical liver enzyme markers like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, histological studies, and physical parameters (liver weight, liver volume, and body weight).
Results: The combination of aripiprazole with fluvoxamine at both TD and MTD showed the hepatic damage and significant elevation in serum transaminase level which is supported by histological reports. The coadministration of aripiprazole with carbamazepine leads to significant decrease in blood concentration of aripiprazole possibly due to induction of enzyme CYP3A4 resulting in loss or reduction of clinical efficacy.
Conclusions: There would be an accumulation of aripiprazole when coadministered with fluvoxamine, a known inhibitor of CYP3A4, leading to hepatic damage and reduction in aripiprazole when administered along with carbamazepine. Therefore, aripiprazole with fluvoxamine and carbamazepine should be coprescribed with caution. The patients should be monitored for signs of adverse effects like hepatic damage or decreased efficacy of these drugs.


Keywords: Aripiprazole, antipsychotic drug, carbamazepine, drug-drug interaction, fluvoxamine, hepatotoxicity


How to cite this article:
Shastry CS, Shafeeque AA, Ashwathnarayana BJ. Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals. Indian J Pharmacol 2013;45:121-5

How to cite this URL:
Shastry CS, Shafeeque AA, Ashwathnarayana BJ. Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals. Indian J Pharmacol [serial online] 2013 [cited 2021 Feb 25];45:121-5. Available from: https://www.ijp-online.com/text.asp?2013/45/2/121/108280



 » Introduction Top


The term psychosis refers to a variety of mental disorders characterized by one or more of the following symptoms: Diminished and distorted capacity to process information and draw logical conclusions, hallucinations, delusions, incoherence or marked loosening of associations, catatonic or disorganized behavior, and aggression or violence. Antipsychotic drugs lessen these symptoms regardless of the underlying cause or causes. [1] Antipsychotic drugs are classified as typical or first-generation antipsychotic agents that were originally developed (clozapine, haloperidol, etc) and as atypical antipsychotic agents which are more recently developed (aripiprazole, ziprasidone, quetiapine, risperidone, paliperidone, etc). [2] Atypical antipsychotics have advantages over typical antipsychotics due to their better safety and efficacy. A combination of antipsychotics may also be an option for some refractory patients. [3]

Most antipsychotic agents like aripiprazole are extensively metabolized in the liver by group of enzymes cytochrome P450 (CYP) which consists of a family of closely related 57 isoforms. [4] Coadministering the drugs which either inhibit or induce CYP enzymes with these antipsychotic agents may result in higher plasma level with adverse effects (mainly hepatic damage) or lower plasma level with compromised therapeutic effect. [5] Hence care must be taken while choosing antipsychotic drugs in combination with other drugs which are also metabolized by these hepatic enzyme. Antidepressant drugs (tricyclic agents or selective serotonin reuptake inhibitors) and mood-stabilizing agents have been extensively coprescribed with antipsychotic agents in treatment of psychosis with bipolar affective disorders, generalized tonic clonic seizures, obsessive compulsive disorders, and depression. These combination are implicated in clinical hepatotoxicity. [6]

The aripiprazole, a quinolinone derivative, shows activity at dopamine D2 and serotonin type 1 (5-HT 1A ) and type 2 (5-HT 2A ) receptors. However, aripiprazole differs from other atypical antipsychotic agents as it demonstrates partial agonistic activity at D2 and 5-HT 1A receptors and antagonistic activity at 5-HT 2A receptors. [7] It is metabolized in liver by enzymes CYP3A4 and CYP2D6.

Carbamazepine has both antiepileptic and psychotropic properties. It stabilizes the inactivated state of sodium channels and decreases excitability of brain cells. It acts on GABA receptors and is used in epilepsy, pain syndromes, and manic depressive illness unresponsive to lithium. [8] It induces the expression of the hepatic microsomal enzyme system CYP3A4. [9]

Fluvoxamine is a potent and selective serotonin reuptake inhibitor that acts by increasing the level of serotonin in the brain. Fluvoxamine, a known inhibitor of CYP3A4, is strongly metabolized in the liver. [10],[11] It is indicated in major depression and anxiety disorders like obsessive compulsive disorder, panic disorder, social phobia, and post-traumatic stress disorder.

Atypical antipsychotics like aripiprazole, used for the long-term treatment of psychosis in combination with other drugs which induce or inhibit hepatic enzyme CYP3A4 may lead to loss of activity or hepatotoxicity. To the best of our knowledge, no studies regarding the hepatotoxic effect of aripiprazole when given in combination with carbamazepine and fluvoxamine are reported. Hence this study was conducted to evaluate the drug-drug interaction among aripiprazole, carbamazepine, and fluvoxamine.


 » Materials and Methods Top


Chemicals

Aripiprazole was a gift sample from Elite pharmaceuticals, Gujarat, and carbamazepine IP and fluvoxamine maleate BP from SUN Pharmaceuticals Industries Ltd, Gujarat. The biochemical parameters estimating kits for total bilirubin, ALP, SGOT, and SGPT were procured from Agappe Diagnostics Ltd., Kerala. Carboxymethylcellulose (CMC) was procured from LOBA Chemie Pvt. Ltd, Mumbai. All other chemicals were of analytical grade. Aripiprazole, carbamazepine and fluvoxamine were prepared freshly in distilled water by suspending with 0.6% CMC before administration to animals orally for 8 weeks.

Animals

All the experiments were carried out in Sprague-Dawley rats of 150-200 g. Animals were kept in the animal house of NGSM Institute of Pharmaceutical Sciences, Mangalore, under controlled conditions of temperature (23±2°C), humidity (50±5%) and 12-h light-dark cycle. Animals were fed pellet diet (Venkateshwara Enterprises, Bangalore) and water ad libitum. All the animals were acclimatized for 7 days before the study. The experimental protocol was approved by institutional animal ethical committee (approval number: KSHEMA/AEC/37/2010)

Selection of Drug Doses

The selection of doses were done based on the human prescribing doses, such as TD and MTD and these human dosages were converted to animal doses as per the conversion chart. [12]

Chronic treatment model for assessment of hepatotoxicity [13],[14]

In this model, animals were treated with two different doses, TD and MTD. For administrating for each dose, the animals were divided into four groups, of six rats each as follows:

Experimental design for therapeutic dose (TD)

Groups Drug treatment and Doses

Group I Vehicle control (received saline 10 ml/kg p.o.)

Group II Aripiprazole (1.35 mg/kg/day p.o)

Group III Aripiprazole (1.35 mg/kg/day p.o) + Carbamazepine (54 mg/kg/day p.o.)

Group IV Aripiprazole (1.35 mg/kg/day p.o) + Fluvoxamine (9 mg/kg/day p.o)

Experimental design for maximum therapeutic dose (MTD)

Groups Drug treatment and Doses

Group I Vehicle control (received saline 10 ml/kg p.o.)

Group II Aripiprazole (4.05 mg/kg/day p.o)

Group III Aripiprazole (4.05 mg/kg/day p.o) + Carbamazepine (144 mg/kg/day p.o.)

Group IV Aripiprazole (4.05 mg/kg/day p.o) + Fluvoxamine (27 mg/kg/day p.o)

Animals were treated with the drugs orally for a period of 8 weeks. After the last treatment, the animals were sacrificed. Blood samples were collected by the cardiac puncture method. The liver was isolated, washed in normal saline, weighed immediately, stored in 10% formalin, and proceeded for histological studies to evaluate the details of hepatic architecture in each group microscopically. The blood was centrifuged, serum separated, and subjected to analysis of the following parameters:

  • Biochemical parameters: SGOT, SGPT, ALP, and total bilirubin
  • Physical parameters: Liver weight, liver volume, and body weight
  • Histological studies of liver
Evaluation of disease

The liver damage in the experimental animals were evaluated based on physical parameters, biochemical parameters and histological studies

Physical parameters

The liver damage was evaluated by parameters like decrease in body weight and increase in liver weight. The body weight of the experimental animals was recorded before and after chronic treatment and the percentage change in body weight was taken for the evaluation of liver damage. After the last dose, animals were sacrificed and the liver weight along with liver volume was also measured.

Biochemical parameters

The biochemical liver enzyme markers like SGOT, SGPT, ALP, and total bilirubin were estimated for the quantification of liver damage by blood samples (which are collected by the cardiac puncture) after the last dose.

Histological Studies

Pieces of liver from each lobe were fixed in Bouin's fluid for 24 h and washed in running tap water to remove the color of Bouin's fluid and dehydrated in alcohol in ascending and descending order, embedded in paraffin, and cut at 5 μm (Automatic tissue processor) in a rotary microtome. These sections were deparaffinized in xylene, stained with hematoxylin-eosin dye, and mounted with Canada balsam. The histological slides were examined and photographs were taken with a digital stereomicroscope (Olympus).

Statistical Analysis

All data were expressed as mean±standard error of the mean (S.E.M.). One-way analysis of variance (ANOVA) followed by Tukey's post test were used for statistical analysis using Graph pad prism 5.0. The minimal level of significance was identified at P < 0.05.


 » Results Top


Chronic treatment model for assessment of hepatotoxicity. The liver weight, liver volume, and body weight were evaluated to determine the liver damage. There was a significant increase (P < 0.01) in the liver weight and liver volume of animals in aripiprazole with fluvoxamine group at both the TD and MTD levels when compared to aripiprazole alone treated group indicating a liver damage. A significant decrease in body weight (expressed as percentage change in body weight) in aripiprazole with fluvoxamine group at both the TD and MTD levels was observed when compared to aripiprazole alone treated group [Table 1], [Table 2] and [Table 3].
Table 1: Effect of combination of aripiprazole with carbamazepine and fluvoxamine on physical parameter (liver weight and liver volume) in rats at TD and MTD

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Table 2: Effect of combination of aripiprazole with carbamazepine and fluvoxamine on physical parameter (body weight) in rats at TD

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Table 3: Effect of combination of aripiprazole with carbamazepine and fluvoxamine on physical parameter (body weight) in rats at MTD

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There was highly significant (P < 0.01) elevation in SGOT, SGPT, and ALP level in aripiprazole with fluvoxamine group at both TD as well as MTD levels and no such elevations were observed in aripiprazole with carbamazepine treated groups. There was also a significant (P < 0.05) increase in total bilirubin level in aripiprazole with carbamazepine groups at TD. Highly significant elevations (P < 0.01) were observed at their MTD when compared to that of aripiprazole alone treated rats. The results of elevation in biochemical liver enzyme markers indicate the hepatic damage [Table 4] and [Table 5].
Table 4: Effect of combination of aripiprazole with carbamazepine and fluvoxamine on biochemical parameters at TD

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Table 5: Effect of combination of aripiprazole with carbamazepine and fluvoxamine on biochemical parameters at MTD

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Histological examination of liver in control group shows the maintenance of normal lobular architecture, normal histology. In groups treated with aripiprazole alone at TD, there was no significant portal inflammation or hepatocytes damage, but at MTD, the portal tract showed small aggregates of chronic inflammatory cells. In the group treated with aripiprazole with carbamazepine at TD, insignificant portal inflammation or hepatocellular damage were seen, but at their MTD there were small aggregates of chronic inflammatory cells and mild periportal inflammation was observed. In the group treated with aripiprazole with fluvoxamine at TD, the portal tract showed small aggregate of chronic inflammatory cells and moderate portal inflammation, but at MTD moderate to severe portal inflammation was observed which confirms the severe hepatic damage in group treated with aripiprazole with fluvoxamine [Figure 1].
Figure 1: Histological examination of liver of different groups

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 » Discussion Top


Liver is the primary site for drug metabolism. Cytochrome P450 is the most important family of metabolizing enzymes present in the liver. Many substances can influence CYP enzyme mechanism by induction or inhibition leading to impaired liver function. [15] Hepatotoxicity is one of the most frequently reported adverse drug reaction. Hepatotoxic drugs can injure the hepatocytes via free radicals that initiate and propagate tissue damage. It is estimated that 15-40 % of acute liver failure (ALF) cases may be attributable to drugs. [16] More than 1000 drugs are known to cause hepatic side effects; 16% of these agents are neuropsychiatric drugs. [6]

Introduction of atypical antipsychotic such as clozapine, risperidone, olanzapine, quetiapine, and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, involving the CYP enzymes. [17] Atypical antipsychotic drugs commonly cause asymptomatic increase in the liver enzymes and serum bilirubin levels, but rarely cause serious hepatotoxicity. [18]

The present study revealed the effect of atypical antipsychotic drug aripiprazole on hepatic function when administered along with carbamazepine and fluvoxamine in experimental animals.

Aripiprazole, used for the long-term treatment in psychosis, is metabolized by three pathways namely dehydrogenation, hydroxylation, and N-dealkylation. Enzymes CYP3A4 and CYP2D6 are responsible for the dehydrogenation and hydroxylation processes and N-dealkylation appears to be catalyzed solely by CYP3A4. [4] Carbamazepine, an antiepileptic drug, is coprescribed in the treatment of psychosis due to its ability to inhibit the symptoms of schizophrenia by its action on GABA-ergic neurotransmission and antikindling action. [19] Carbamazepine causes induction of the hepatic microsomal enzyme system, specially CYP3A4 leading to significant decrease in the blood concentration of aripiprazole. This might result in the loss or reduction in clinical efficacy. [9],[20] Fluvoxamine is involved in clinically relevant pharmacokinetic interactions with many medications, involving antipsychotics [21] and with aripiprazole it leads to accumulation due to its inhibitory action on CYP3A4 enzyme, and consequent hepatic damage. [10]

The present study revealed increased level of biochemical parameters like SGOT, SGPT, and ALP indicating significant liver damage when aripiprazole was administered in combination with fluvoxamine at both TD as well as MTD levels. The histological studies of liver show chronic inflammatory cells and portal inflammation supports liver damage. The increase in liver weight, liver volume, and decrease in body weight further strengthen the drug-induced liver damage by the combination of aripiprazole with fluvoxamine. However, there is no such significant damage to liver when aripiprazole given in combination with carbamazepine.

Thus it may be concluded that there was significant hepatotoxicity when aripiprazole was given in combination with fluvoxamine possibly due to inhibition of aripiprazole-metabolizing enzyme CYP3A4. Similarly coadministration of carbamazepine, a CYP3A4 inducer may lead to significant decrease in plasma concentration of aripiprazole due to which there will be increase in aripiprazole metabolism and potentially a loss in clinical efficacy.

Hence care should be taken while prescribing aripiprazole with fluvoxamine and carbamazepine for treatment of psychosis. Monitoring adverse effects like hepatotoxicity or decreased efficacy is required. Titration and correction of dose may be necessary in such case.

 
 » References Top

1.Lasley SM. Antipsychotic drugs. In: Craig CR, Stitzel RE, editors. Modern pharmacology with clinical applications. 6 th ed. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 397.  Back to cited text no. 1
    
2.Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. 6 th ed. Philadelphia: Churchill Livingstone Elsevier; 2007. p. 548.  Back to cited text no. 2
    
3.Melnik T, Soares BG, Puga ME, Atallah AN. Efficacy and safety of atypical antipsychotic drugs (quetiapine, risperidone, aripiprazole and paliperidone) compared with placebo or typical antipsychotic drugs for treating refractory schizophrenia: Overview of systematic reviews. Sao Paulo Med J 2010;128:141-66.  Back to cited text no. 3
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4.Urichuk L, Prior TI, Dursun S, Baker G. Metabolism of atypical antipsychotics: Involvement of cytochrome P450 enzymes and relevance for drug-drug interactions. Curr Drug Metab 2008;9:410-8.  Back to cited text no. 4
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5.Sharif ZA. Pharmacokinetics, metabolism and drug-drug interactions of atypical antipsychotics in special populations. Prim Care Companion J Clin Psychiatry 2003;5 Suppl 6:22-5.  Back to cited text no. 5
    
6.Dumortier G, Cabaret W, Stamatiadis L, Saba G, Benadhira R, Rocamora JF, et al. Hepatic tolerance of atypical antipsychotic drugs. Encephale 2002;28:542-51.  Back to cited text no. 6
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7.DeLeon A, Patel NC, Crismon ML. Aripiprazole: A comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther 2004;26:649-66.  Back to cited text no. 7
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8.Borges A, Abrantes JB, Penha JM, Parada PP, Teixeira MT, Teresa M. Carbamazepine. Available from: http://www.inchem.org/documents/pims/pharm/pim100.html. [Last accessed on 1999 Nov].  Back to cited text no. 8
    
9.Citrome L, Macher JP, Salazar DE, Mallikaarjun S, Boulton DW. Pharmacokinetics of aripiprazole and concomitant carbamazepine. J Clin Psychopharmacol 2007;27:279-83.  Back to cited text no. 9
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10.Olesen OV, Linnet K. Fluvoxamine-clozapine drug interaction: Inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism. J Clin Psychopharmacol 2000;20:35-42.  Back to cited text no. 10
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11.Barr Laboratories Inc. Fluvoxamine official FDA information, side effects and uses. Fluvoxamine-clinical pharmacology-pharmacokinetics 2011;2:15.  Back to cited text no. 11
    
12.Ghosh MN. Fundamentals of experimental pharmacology. 4 th ed. Kolkata: Hilton and Company; 2008: p. 178.  Back to cited text no. 12
    
13.McLean EK, McLean AE, Sutton PM. Instant cirrhosis. An improved method for producing cirrhosis of the liver in rats by stimulus administration of carbon tetrachloride and pentobarbitone. Br J Exp Pathol 1969;50:502-6.  Back to cited text no. 13
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14.Yadav MS, Kumar A, Singh A, Sharma US, Sutar N. Phytochemical investigation and hepatoprotective activity of cissampelos pareira against carbon-tetrachloride induced hepatotoxicity. Asian J Pharm Health Sci 2011;1:106-10.  Back to cited text no. 14
    
15.Michalets EL. Update: Clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;18:84-112.  Back to cited text no. 15
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16.Walker R, Whittlesea C. Clinical pharmacy and therapeutics. 4 th ed. Philadelphia: Churchill Livingstone Elsevier; 2007: p. 231.  Back to cited text no. 16
    
17.Prior TI, Chue PS, Tibbo P, Baker GB. Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 1999;9:301-9.  Back to cited text no. 17
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18.Atasoy N, Erdogan A, Yalug I, Ozturk U, Konuk N, Atik L, et al. A review of liver function tests during treatment with atypical antipsychotic drugs: a chart review study. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1255-60.  Back to cited text no. 18
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19.Hosak L, Libiger J. Antiepileptic drugs in schizophrenia: A review. Eur Psychiatry 2002;17:371-8.  Back to cited text no. 19
    
20.Citrome L, Macher J, Salazar DE, Mallikaarjun S, Boulton DW. Pharmacokinetics of aripiprazole and concomitant Carbamazepine. J Clin Psychopharmacol 2007;27:279-83.  Back to cited text no. 20
    
21.Spina E, Santoro V, D'Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: An update. Clin Ther 2008;30:1206-27.  Back to cited text no. 21
[PUBMED]    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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