الفهرس 
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Abstract
Drug-drug interaction is considered one of the most important complications that could cause death. Many people take more than one drug at the same time without any awareness about their interaction or effect on human body. One of the most usable drug for treating epilepsy is carbamazepine which is taken for long time and it is very possible that the patient would need an analgesic for any reason during this longtime. Acetaminophen (APAP) is a widely used over-the-counter analgesic and antipyretic. When the patient takes two drugs without any knowledge about what may happen especially if the two drugs share the same metabolic enzymes.
CBZ is metabolized mainly by CYP3A4 to give an active metabolite; carbamazepine10,11-epoxide, and APAP is metabolized mainly by sulphation and glucuronidation pathways and about 5% of APAP is excreted unchanged, the remaining 5–10% is metabolized via oxidation by CYP3A4 and CYP2E1 to form the toxic metabolite NAPQI which is detoxified by liver GSH. Both of the two drugs cause hepato- and nephron-toxicity.
Here we use two agents to prevent or ameliorate the detrimental effects that result from the interactions between CBZ and APAP. REE and CoQ10 were used as curative or preventive agents because of their ability to increase the body defense mechanisms by enhancing the antioxidant system to overcome this toxicity.
To determine the effect of the two drugs combination, we evaluated some biochemical parameters such as liver alanine aminotransferase, kidney function tests (urea and creatinine), antioxidant parameters (MDA, SOD, CAT, GST, GSH, and GPx), PCR analysis for the enzymes responsible for CBZ& APAP metabolism (CYP3A4, CYP2E1), liver and kidney cytokines (TNF-α, IL-6, and IL-1B), histopathology of liver and kidney tissue and determination of plasma clearance of both drugs using HPLC.
To achieve the goal, the rats were randomly divided into ten equal groups (n = 6, each) numbered from A to J, respectively. Animals were treated orally with CBZ (108 mg/kg/d) APAP (360 mg/kg/d), CoQ10 (6 mg/kg/d) and REE (100 mg/kg/d) as follow:
1-group (A) control group: This group received a daily dose of 5% tween 80 in saline for 14 days.
2-group (B) CBZ: Animals received a daily dose of CBZ for 14 days.
3-group (C) APAP: Animals received a daily dose of APAP for 10 days.
4-group (D): Animals received CBZ daily for 14 days and APAP from day 5 to day 14.
5-group (E) REE: Animals received REE for 10 days.
6-group (F) CoQ10: Animals received CoQ10 for 10 days.
7-group (G) REE pre-APAP treated group: Animals received a daily dose CBZ for 14 days. from day 5 to day 14, they received REE then APAP.
8-group (H) CoQ10 pre-APAP treated group: Animals received a daily dose CBZ for 14 days. from day 5 to day 14, they received CoQ10 then APAP.
9-group (I) REE post-APAP treated group: Animals received CBZ daily for 14 days. Starting from day 5 to day 14, they received APAP then REE.
10-group (J) CoQ10 post-APAP treated group: Animals received CBZ daily for 14 days. Starting from day 5 to day 14, they received APAP then CoQ10.
The co-administration of CBZ and APAP caused hepato-toxicity and nephron-toxicity. This was typified in the liver and kidney function tests which increased in this group. Also the liver antioxidants have been affected; liver GSH, GST, and GPx were decreased and MDA was increased but CAT and SOD were not affected by the combined administration of CBZ& APAP. The expression of enzymes responsible for CBZ& APAP metabolism; CYP3A4 and CYP2E1were not affected by their combination. The pro-inflammatory cytokines expressions were also affected by different pattern for liver and kidney. Liver IL6 and TNF-α expression were decreased but IL1β was not affected. Kidney IL6 was decreased but TNF-α and IL1β were not affected by the combination of CBZ& APAP. They also delayed the elimination time for each other, which was determined by HPLC for both drugs. The histopathological examination of liver and kidney showed evident toxicity signs resulted from treatment with CBZ and APAP.
Both of REE and CoQ10 used with combination of CBZ+APAP by two ways; before APAP as a preventive agent and after APAP as a curative agent. In the two regimens, they helped in decreasing liver ALT. REE decreased creatinine and urea levels when taken before APAP. CoQ10 increased creatinine when taken after APAP. Liver MDA and GST were decreased, while SOD, CAT, and GPx were not affected in the groups treated with REE or CoQ10 after and before APAP with CBZ. Both REE and CoQ10 increased GSH level when added after APAP with CBZ (as a curative agent). Also they did not affect the expression of liver CYP3A4, TNFα, and IL1β, but only CoQ10 that increased the expression of CYP2E1. Liver IL6 increased in the groups treated with REE after APAP and CoQ10 before APAP. In the kidney, TNFα was not affected unlike IL1β that had decreased in the last three groups (CBZ+ CoQ10+ APAP), (CBZ+ APAP+ REE), and (CBZ + APAP+ CoQ10). Kidney IL6 increased in the group that received CoQ10 before APAP.
The histopathology of liver tissue in the groups treated with CBZ, APAP, CBZ+APAP showed severe dilation in the central vein with ballooning degeneration in the surrounding hepatocytes and the portal vein showed inflammatory cells infiltration and necrosis. Groups of REE or CoQ10 did not affect the histology of liver tissue when given alone. REE ameliorated the hepatotoxicity and abolished the necrosis of liver tissue only when given after APAP with CBZ, but when given before APAP, it did not exert the same effect. CoQ10 when administered after and before APAP with CBZ caused severe dilation, congestion and necrosis. The histopathology of the kidney tissue from the APAP-treated group did not show any alteration unlike the groups treated with CBZ alone or combined with APAP that showed cystic dilation and degeneration in the lining epithelium. REE and CoQ10 ameliorated these effects.
Treatment with REE or CoQ10 decreased the nephrotoxicity manifested in the normalization of the histopathological examination. On the other hand, only REE when added after APAP ameliorated the hepatotoxicity by restoring the normal elimination time for both drugs which is the only group that did not show any histological alteration unlike the group treated with REE before APAP and the groups treated with CoQ10.
Conclusions
CBZ+APAP caused hepatotoxicity, lipid peroxidation, oxidative stress, and disturbed the tissue architecture of liver. They reduced the pro-inflammatory cytokines. REE and CoQ10 were able to alleviate most of these detrimental effects through enhancing the cellular antioxidant milieu, induction of metabolizing enzymes, reduction of the plasma half-life of APAP and CBZ preventing their accumulation and potential interaction. In many instances, REE offers superior protection to that of CoQ10.