Circumvention of Hepato-toxicity of Paracetamol by Co-administering with Flavonoids in the treatment of Osteoarthritis

doi:10.21203/rs.3.rs-4955542/v1

Objectives

The objective of present study is to develop novel pharmaceutical dosage form to reduce the hepatotoxicity of Paracetamol when induced in higher doses in treatment of Osteoarthritis. The effect of Quercetin in controlling paracetamol toxicity was planned to be studied by conducting in vivo studies on rats for 21days¹. The outcome of the present study is to show that Quercetin shows high impact in reducing the hepatotoxicity caused by paracetamol due to release of toxic metabolite NAPQI by cytochrome P-450 during metabolism process.

Materials and methods

Rats were treated with Paracetamol in combination with different dose strengths of quercetin, and with silymarin as standard.

Results

Quercetin is given in doses of 5, 10, and 15 mg/kg body weight. with paracetamol lowered the blood levels of SGOT, SGPT, ALP, DB, and TB while restoring albumin & total protein levels to normal in a dose-varying way in comparison to the toxic control. Histopathology of liver and kidney were done for cell necrosis². Chrsyin therapy at low doses resulted in a modest recovery from necrosis, vacuolization, inflammation, and fatty alterations. Moderate recovery from necrosis, vacuolization, lipid alterations, and inflammation was observed with medium dose therapy³. Treatment at a high dose maintained the liver's natural architecture.

Conclusion

The current study found that Quercetin inhibits the CYP2E1 mediated metabolism, as a result reduces the formation of toxic metabolite NAPQI by suppressing the liver and kidney biomarkers⁴. Hence reducing the liver toxicity

Cytochrome P-450

Paracetamol

NAPQI

Quercetin

Osteoarthritis is the most prevalent kind having the risk of mobility impairment.¹ Mechanical considerations play a major part in the multifactorial process of osteoarthritis (OA) which is distinguished by modifications in the joints with regard to the overall structure and functionality.⁵Osteoarthritis is of two groups: primary and secondary type. Although OA displays as soreness in the joints and loss of functionality, the severity is clinically extreme⁶. Water makes up the majority of cartilage's composition (70%) along with a type II collagen framework, proteoglycans, and glycosaminoglycan’s. The synovium supplies nutrients to the chondrocytes through diffusion, and further joint movements facilitate the circulation of synovial fluid. In people with osteoarthritis, paracetamol is effective in terms of reducing pain and enhancing physical performance⁷. Since NSAID usage for long period of time increases the risk of cardiovascular and gastrointestinal adverse effects^8.9.10. Hence, paracetamol is often the first-line therapy for mild to moderate pain management in osteoarthritis. However, paracetamol is taken more frequently ^11,12

Flavonoids are phenolic compounds with biological properties including antiallergenic, antiviral, anti-inflammatory, and vasodilating effects^13,14. "Flavus," which meaning yellow in Latin, is where the term flavonoids originate. Flavonoids have the capacity to snare free radicals and prevent lipid peroxidation.¹³Quercetin is a vital bioflavonoid that is found in more than 20 different plant species ¹⁵ .Quercetin is an aglycone type of flavonoid glycosides that is obtained from plants and has been used as a dietary supplement^16,17.

Natural antioxidants can avert liver damage through the inhibition of the inflammatory response or by scavenging toxins and other oxygen species. Further research has demonstrated that flavonoids like silymarin reduce hepatotoxicity caused by xenobiotics¹⁸. A complex blend of flavonolignans, silymarin is the main bioactive ingredient of Silybum marianum. It has been shown to have protective properties against xenobiotics, especially the liver. Because silymarin is an antioxidant, it inhibits lipid peroxidation and preserves cell membranes, all of which contribute to its hepatoprotective effects. Another natural flavonoid is chysin (5,7-dihydroxyflavone)¹⁹. The presence of chysin, which has not been examined as thoroughly as silymarin, is known to be high in propolis, honey, and other plant extracts. Researchers have found that chrysin possesses anti-allergic properties²⁰.

Present study is conducted to explore the ability of paracetamol in treatment of Osteoarthritis and also reducing the toxicity of paracetamol when taken in repeated doses. Paracetamol in combination with chrysin is chosen in different formulations and conducted invivo studies on rats for 21 days^21,22. blood samples have been collected at various time intervals. Effect of paracetamol individually and along with flavonoids (chrysin) were identified by conducting biochemical analysis of blood samples to find out changes in liver and kidney biomarkers and also histopathological studies to check out cell necrosis and tissue damage^23,24,25.

2.1 Materials

Paracetamol as a gift sample from Aurobindo pvt ltd, used as active ingredient. Quercetin is brought from SISCO Laboratories Pvt Ltd. Ethyl alcohol purchased from SD Chemicals Pvt Ltd; sodium carboxy methyl cellulse purchased from SD fine chemicals; micro crystalline cellulose purchased from Yogi Dye Chemical Industries.

2.2 Experimental animals

Animal studies were carried out under the guidelines and approval issued by animal’s ethical committee of Vignan University(VFSTR) vadlamudi, Guntur, A.P, India. Male Wister rats, weighed between 200g and 250 g and at least two months old, were placed in an air-conditioned room at 25 ± 2°C with a 12-hour light/dark cycle and unrestrained access to food and water. Standard feed was used to feed the animals (VRK Nutritional Solutions, Mumbai, India). Every animal ingested 15 g of feed on an average each day. The animals were procured from VFSTR Animal house. Before conducting the study animals were treated according to standard laboratory conditions. The approved protocol number is VFSTR 2046/1AEC/V/2023-5

2.3 Experimental Design

The current study used Wistar rats for the in vivo studies. Rats were treated by paracetamol and also in combination with Quercetin and silymarin for period of 21days. Rats were separated into 3 groups having 4 rats in each group. First group is treated with Paracetamol alone; second group is treated with silymarin (CYP2E1 inhibitor), third group treated with Paracetamol in combination of Quercetin through the oral route

2.4 Invivo Studies on Wistar Rats

Wister rats were split up into six groups, each consisting of four rats.

Group-1: Rats were treated with 1% Sodium carboxy methyl cellulose (Normal)

Group-2: Rats were treated with Paracetamol (Pcm) alone (80mg/kg body weight) (Negative control)

Group-3: Rats were treated with Silymarin followed by treatment with Pcm (Positive control)

Group-4: Rats were initially given treatment with Quercetin (5mg/kg) followed by treatment with Pcm (80mg/kg body weight)

Group-5 Rats treated with Quercetin (10mg/kg) followed by treatment with Pcm (80mg/Kg body weight)

Group-6 Rats treated with Quercetin (15mg/kg) followed by treatment with Paracetamol (80mg/kg body weight)

At the end of the 21st day, 1 milliliter of blood was drawn from each rat in sterilized Eppendorf tubes at different time intervals of 0.3,1, 2,4,6,8,10,12hrs. Blood samples were taken and kept at -20°C. Centrifugation was performed to blood samples for 12 minutes at 10,000 RPM. to extrude out the plasma from blood

2.5 Calculation of Pharmacokinetic Parameters

Pharmacokinetic parameters Area under the plasma concentration-time curve from 0 to the last quantifiable concentration's time, Maximum plasma concentration, Findings included the area under the plasma metabolite concentration-time curve from zero to infinity, the time it takes to reach peak plasma concentration, the terminal half-life, the mean residence time, the apparent oral or total body clearance, the apparent volume of distribution at steady state for paracetamol, and the amalgamation of paracetamol with quercetin and silymarin.

2.6 Biochemical Analysis

From each rat's orbital sinus, blood samples were taken.. Blood samples were taken both before and after treatments in order to compute the biochemical parameters. The assessment of biochemical parameters was done using the serum that emerged after centrifugation.

Using the IFCC method SGOT, SGP and ALP were computed. Uric acid was identified using the uricase method, and urea was determined using the urease–GLDH method

Using established techniques, we calculated TP, TB, BUN, and creatinine.

2.7 Histopathological Studies

Rats were sacrificed under isoflurane anaesthesia. after overnight fixation (12hrs) of the tissue samples in 10% formalin solution, the tissue is processed for cell block preparation.

Steps in the processing of the cell block preparation

70% Ethyl alcohol for 1hr, 95% Ethyl alcohol 1hr, 95% Ethyl alcohol 30min, 95% Ethyl alcohol 30min, Absolute Ethyl alcohol 1hr, Absolute Ethyl alcohol 2 times 1hr each, Xylol 2 times 1hr each, Paraffin 1hr, Paraffin bath for at least 2hr. Precautions taken to prevent any artifacts due to technical problems. As delay in fixation could cause air drying artifacts like giving nuclei pale staining, cytoplasmic and nuclear eosinophilia, the samples were processed as soon as the samples were received in the lab. All the alcohol and xylene grades were filtered everyday using Whatman filter paper and the fixatives were filtered after each case. Samples of tissue from the kidney and liver Thin sections of 3–5 micron thickness were cut from the cell blocks made using a rotary microtome. they were cleaned with NaCl 0.9% solution. Samples of the Kidney (0.1 g) and liver (0.3 g) had been blotted and stored at range of -80 ◦C and homogenizing the tissues in phosphate buffer (pH 7.4) for biochemical analyses, followed by a fifteen-minute centrifugation at 3000 rpm at 4°C.. preserved with paraffin wax and 10% (v/v) formaldehyde, then stained for histological analyses using haematoxylin and eosin stain. The histopathological examination was carried out for animal groups. A semi-quantitative tests approach, as suggested by Dixon et al, was employed to evaluate the pathological changes were recorded. Under a photomicroscope, the kidney sections have been examined for signs of kidney damage, such as cellular necrosis, tubular deterioration, glomerular hyper cellularity, capillary congestion, and haemorrhaging

Rats which are treated with 80 mg/kg of paracetamol and displaying significant hepatocyte necrosis in the parenchyma area, in addition to steatosis and bleeding, leukocyte infiltration, and sinusoid dilatation, were identified to be of critical significance for the liver histopathological reports.

3.1 Effect of Quercetin on Pharmacokinetics of Paracetamol

Table:1 Pharmacokinetic parameters of three distinct formulations of paracetamol alone and in combination with quercetin

Parameter	Paracetamol (80 mg/kg)	Paracetamol + silymarin (100 mg/kg)	Paracetamol + Quercetin (5 mg/kg)	Paracetamol + Quercetin (10 mg/kg)	Paracetamol + Quercetin (15mg/kg)
Cmax	9.012 ± 0.234	10.212 ± 0.322	11.012 ± 0.001	11.012 ± 0.223	13.912 ± 0.322
AUC0–12 (µg/ml × h)	52.431 ± 0.344	61.571 ± 0.813	52.431 ± 0.945	63.431 ± 0.234	67.91 ± 0.43
AUC0-∞ (µg/ml × hr)	45.021 ± 0.98	55.016 ± 2.761	63.021 ± 0.654	79.021 ± 1.345	88.021 ± 1.00
tmax (hr)	1.321 ± 0.123	1.112 ± 1.234	1.0382 ± 0.974	1.003 ± 0.452	1.001 ± 0.004
t1/2 (hr	1.923 ± 0.098	2.219 ± 0.743	3.923 ± 1.832	3.923 ± 0.004	6.923 ± 1.234
MRT (hr)	6.313 ± 0.341	6.931 ± 0.533	6.313 ± 0.532	6.313 ± 1.757	6.313 ± 0.943
CL/F (ml/hr	0.292 ± 1.324	0.112 ± 0.115	0.281 ± 1.945	0.212 ± 0.013	0.145 ± 0.211
Vz/F	2.193 ± 0.375	1.476 ± 0.44	1.943 ± 0.75	1.635 ± 1.335	1.145 ± 0.843
Vss/F	2.653 ± 1.384	1.673 ± 0.067	1.983 ± 0.678	1.876 ± 0.194	1.233 ± 0.255

Abbreviations: C max: Maximum plasma concentration, Area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration, Area under the plasma metabolite concentration-time curve from zero to infinity; t max, time to reach peak plasma concentration; t 1/2, terminal half‐life; MRT, mean residence time; CL/F, apparent total body clearance or oral clearance Vz/F, apparent volume of distribution; Vss/ F, apparent volume of distribution at steady state

3.2 Biochemical Analysis of Paracetamol with flavonoids Effect of Quercetin on Liver biomarkers

Treatment with paracetamol (80 mg/kg) substantially raised blood levels of SGOT, SGPT, ALP, DB, and TB, while lowering total protein and albumin levels compared to the control. In comparison to the toxic control, the use of quercetin at doses of 5, 10, and 15 mg/kg b.wt. in combination with paracetamol reduced blood levels of SGOT, SGPT, ALP, DB, and TB while normalizing total protein and albumin levels in a dose-dependent manner. The impact of quercetin on serum liver indicators is displayed in Figure No. 2.

Rat kidney functioning biomarkers:

The impact of quercetin on their structure
Figure 2 illustrates how quercetin affects serum kidney indicators. Comparing the creatinine, uric acid, and urea levels of the animals treated with 80 mg/kg of paracetamol to those of the normal control, there were slight increases. When quercetin was administered at doses of 5, 10, and 15 mg/kg combined with paracetamol, the patient recovered in a way that was similar to normal healing.

3.3 Histopathology of liver and Kidney

Quercetin is a member of a broad group of plant-derived polyphenolic chemicals. One of the flavonoids that is most commonly found in diets, lovage, red onions, green and black tea, and capers all contain significant amounts of it (Anand David et al., 2016). Numerous research has shown the advantages, but few have questioned the safety of quercetin (Dunnick and Hailey, 1992). quercetin show hepato-protective effects on a variety of pathogens

The present study was carried out to determine quercetin's impact on paracetamol toxicity. Initially rats were treated with paracetamol to identify for the change in liver and kidney biomarkers. Liver activity and its functioning is identified by measuring SGOT, SGPT, TB, ALP, TP. All these biomarkers showed elevated levels than required because of their over flow into blood stream ultimately leads to abnormal activity of liver. Rats which are treated with paracetamol followed by Quercetin

Hepatotoxicity biomarkers (ALT, AST, ALP, and LDH) revealed substantially (p<0.05) elevated values in the quercetin higher dosage group (Group Il) compared to the control group, suggesting the onset of hepatotoxicity at these dosages. Animals in Group II had significantly greater ALP levels (p<0.05) than those in Group I, the control group.

The liver sections showed uniformly distributed normal hepatocytes with the bile duct, hepatic artery, and central vein when the dose concentrations in Group III and Group IV animals were compared to the control (Group I). Histological alterations were also absent. No significant damaged areas were observed in Group V animals; instead, only hydropic changes, including ballooning and degeneration in hepatocytes, were observed.

High dose treatment groups (Groups III, IV, and V) showed a substantial reduction in reduced glutathione content (GSH). Glutathione content in the quercetin dosing group (Group II) remained unchanged as compared to the reports identified in control group.

It has been demonstrated by evidence that all the hazardous & nephrotoxicity) has been linked to the use of paracetamol.. Within this research, the impact urea measurements to look at the effects of quercetin on renal function. Urine, blood urea nitrogen, and creatinine. These findings showed that blood urea, creatinine, uric acid, and serum urea levels after taking paracetamol, nitrogen levels increased, identifying renal issues.

Quercetin was shown to dramatically enhance the plasma concentrations, AUC, Cmax, and MRT of valsartan in another investigation (Challa et al., 2013). This increase may have been caused by inhibition of CYP3A4 and P-gp. Due to CYP3A4 and P-gp inhibition, quercetin increased the bioavailability, AUC, Cmax. In the present study It has been discovered that quercetin inhibits CYP3A4 in normal rats. Due to CYP3A4 inhibition, treatment with quercetin increased all pharmacokinetic parameters, including Cmax, AUC, t1/2, and MRT, as compared to the low dose (control group)

The primary objective of the current study was to determine how quercetin affects paracetamol's hepatotoxicity. . Histological examination showed that the positive paracetamol control groups did not exhibit steatosis. On the other hand, rats treated with paracetamol showed necrosis and fibrosis along with polymorph nuclear infiltration seen in the centrilobular area. Quercetin's antioxidative property showed high impact on its hepatoprotective effects on liver damage brought on by paracetamol. Quercetin perhaps acted as an antioxidant, scavenging free reactive oxygen species and preventing the chain reactions of free radicals produced by paracetamol from reaching their hepatic tissue.

Acknowledgements

The authors thank all of the participants in the current experiment for their participation. We would especially like to thank the Pharmaceutics department, vignan university for their enthusiastic participation in this study.

Author information

K Sai Priyanka & Dr G Srikar

Authors and Affiliations

Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan's Foundation for Science, Technology and Research, (VFSTR) Vadlamudi, Guntur 522213, Andhra Pradesh, India.
Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, (VFSTR) Vadlamudi, Guntur 522213, Andhra Pradesh, India.

Corresponding authors

Dr G. Srikar & Ms K Sai Priyanka

Ethics Declarations

Conflict of interest

The authors declare that they have no financial or non-financial competing interests that are directly or indirectly related to this work.

Ethical approval

This study was approved by the Ethics Committee . The animals were procured from VFSTR Animal house. Before conducting the study animals were treated according to standard laboratory conditions. The approved protocol number is VFSTR 2046/1AEC/V/2023-5

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Circumvention of Hepato-toxicity of Paracetamol by Co-administering with Flavonoids in the treatment of Osteoarthritis

Status:

Version 1

Abstract

Objectives

Materials and methods

Results

Conclusion

Figures

1. INTRODUCTION

2. MATERIALS&METHODS

2.1 Materials

2.2 Experimental animals

2.3 Experimental Design

2.4 Invivo Studies on Wistar Rats

2.5 Calculation of Pharmacokinetic Parameters

2.6 Biochemical Analysis

2.7 Histopathological Studies

3 RESULTS

3.1 Effect of Quercetin on Pharmacokinetics of Paracetamol

Discussion

Conclusions

Declarations

References

Status:

Version 1