TOPIC : ANIMAL MODEL OF HEPATOPROTECTIVE DRUG

MAULANA ABUL KALAM AZAD UNIVERSITY OF TECHNOLOGY

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY

PRESENTED BY: SNEHASIS JANA

M.PHARM, PHARMACOLOGY, 1st YEAR,2022-2023
CONTENT:

•Introduction
•Liver toxicity and DILI
•Hepatoprotectives and objective of
hepatoprotective models
•List of hepatoprotectives
•Screening model
•Conclusion
INTRODUCTION
Liver is the largest and important organ in the body, It regulates
different functions in the body, such as metabolism, secretion,
storage and detoxifying.

Metabolism or biotransformation of hepatotoxic agents is a

detoxifying process where molecules are modified into less toxic
shapes by different enzymatic systems.

phase 1 reactions: Oxidations, reductions or hydrolysis

phase 2 reactions: Conjugation reactions, glucuronidation,

acetylation, and sulfation.
LIVER TOXICITY AND DILI
The major cause in india of liver toxicity is ethanol, it is suspected that more than
half of the cases of hepatotocity is due to alcohol. Others chemicals that causes
hepatotoxicity is Carbon tetrachloride, Galactosamine, Thioacetamide.

DILI( Drug induced Liver Injury)

•Anti convulsant- Carbamazepine, valporic acid.

•Anti tubarculosis- all drugs except Ethambutol
•NSAIDS- Paracetamol, Diclofenec, Indomethacin
•Antimicrobial- Ketoconazole
•Miscellaneous: Disulfuram, Isofurane, Doxirubicin
Hepatoprotective and what objective of
Hepatoprotective models
Protecting the liver from the harmful effects of hepatotoxins, which may be
ingested or alterations in the antirradical defense mechanisms, the agents
capable of doing this are called hepatoprotective.

The objective of hepatoprotective models is for the compounds being tested to

counteract or avoid the damage generated by hepatotoxins.

The magnitude of the hepatoprotective effect can be measured

through biochemical makers. e.g Aspartate Aminitransferese, Alanine
Amonitransferase,Alanine Phosphatase, Bilirubin, Total Proteins, Gama
glutamine transpeptidase
LIST OF HEPATOPROTECTIVES

•Acetaminophen
•Penicillamine
•Antioxidant
•Cardiotrophin-1
•S-adenosyl methionine (SAM)
•Herbal medicines (e.g Silybum marianum)
•vaccines
 SCREENING MODEL
CCl4 induced liver toxicity in rats
Principle: CCl4 biotransforms into CCl3 by the cytochrome P-450, which is a toxic metabolite. They produced the
free radicals, that further cause liver necrosis, and histolically observed liver fibrosis.

Procedure: Group of 20 female Wister rats(100-150g) are orally given 1mg/kg CCl4 twice a week, dissolve the drug into

olive oil 1:1 over a period of 8 weeks.

Control group receives only olive oil. Drugs are given twice a day except Sunday. Sunday only one dose is given.

By the end of the 8th week animals are sacrificed using anesthetic eather.

Evaluation: In serum the parameters that are determined are Bilirubin, Total bile acids, Feragments of type
IV collagen.
Histological analysis: 3-5 pices of of liver (about 1 g) are fixed in formalin and each section of liver are
embedded and evaluated for the development of fibrosis using a score of O-IV.

Grade-O: Normal liver histology

Grade-I: Tiny and short septa of connective tissue.
Grade-II: Large septa of connective tissue.
Grade-III: Nodular transformation of the liver.
Grade-IV: Excessive formation and deposition of connective tissue.
Paracetamol induced liver toxicity in rats
Principle: Paracetamol is metabolized by cytochrome p-450 into N-acetyl-p-benzoquinone. That’s
further results in production of oxidative stress and liver damage.

Procedure: Wister rats of (150-200) are given paracetamol 2g/kg body weight by oral route as a single

dose
The animal are given the test drug for 6days for 6 days prior to paracetamol administration and on the 7th
day along with paracetamol

24 hours after of the administration of the drugs the animal are sacrificed.

The biochemical analysis is performed by blood/ serum, and the liver for histopathological studies.
Evaluation: In serum/blood the parameters that are determined are Bilirubin.
The organs rich with the enzyme ALP, ALT and the AST liberation is proportional to the damage generated.
Rifampicin + Isoniazide induced liver toxicity in rats
Principle: As all the anti tubarculosis drugs except ethambutol causes liver toxicity. Then when we use
the drugs combination of Rifampicin and isoniazide it causes liver toxicity.

Procedure:

Wister rats weight about 150-200gm are taken for the experiment.
Rifampicin and Isoniazide both drugs are given in the dose of 50mg/kg body weight of each rat by the
route of I.P injection once a day for 15 days.

The test drug were also administered along with the combination of both drugs(RMP+INH) for 15 days

At the end of the experiment the rats are killed by decapaciation.

Evaluation: The biochemical analysis is performed by blood/serum and histopathology of liver is

performed.
CONCLUSION
Liver diseases are a major health problem, domestically and around the
world. thus, it is necessary to develop new molecules which help counteract
or prevent them.

The discovery and development of new drugs begins with the

demonstration of the pharmacological effects, to later conduct safety and
efficacy studies in human beings.

Thus different types of in-vitro, In-vivo tested are performed. In this slide
we only discussed about 3 types of animal model, apart from that a lots of
experiments is performed for the drug development and discovery model.
References:
•Delgado-Montemayor C, Cordero-Pérez P, Salazar-Aranda R, Waksman-Minsky N. Models of hepatoprotective
activity assessment. Medicina universitaria. 2015 Oct 1;17(69):222-8.

•Weiskirchen R. Hepatoprotective and anti-fibrotic agents: It's time to take the next step. Frontiers in
pharmacology. 2016 Jan 7;6:303.

•Mohamed Saleem TS, Madhusudhana Chetty C, Ramkanth SV, Rajan VS, Mahesh Kumar K, Gauthaman K.
Hepatoprotective herbs–a review. International Journal of Research in Pharmaceutical Sciences. 2010;1(1):1-5.
Thank
You