Acute and Sub-Chronic Toxicity Studies of Recombinant Exenedin-4 in Rats

Sumasri Guntupalli*¹, Gowthami Vangala², Venugopalaiah Penabaka³, Pasupuleti Naresh^3
1Department of Pharmacology, Shri Vishnu College of Pharmacy, Andhra Pradesh, India
²Department of Biotechnology, Virchow Biotech Private Limited,  Hyderabad, India
³Department of Pharmaceutics, Ratnam Institute of Pharmacy, Nellore, Andhra Pradesh, India-524346

Abstract
The acute and sub-chronic toxicity effects of recombinant Exenedin-4 were investigated when administered intravenously and subcutaneously to Sprague Dawley (SD) Rats. For acute toxicity study, the test compound was administered to adult SD Rats with 10 times of intended therapeutic dose for once in 10 (5M+5F) rats through intravenous (IV) route and another group of 10 (5M+5F) rats subcutaneously. The animals were observed for morbidity and mortality after test compound exposure followed by daily observations for a period of 14 days. In the sub chronic dose study the test compound is administered subcutaneously to 7 groups (6M+6F) SD Rats twice daily for a period of 28 days. Physical and physiological examinations, hematology, clinical chemistry, gross necropsy, histopathology, genotoxicity and cytotoxicity profiles were evaluated using the samples collected from the animals. In the acute study, no untoward effects or mortality occurred following acute intravenous and subcutaneous administration of Exendin-4 in SD Rats. In sub chronic toxicity study, no adverse effects such as irritation, inflammation and edema were noticed at the site of injection. Recombinant Exenedin-4 has no effect on food intake, body weight, clinical signs and behavioral activity on animals in all groups. Pre exposure and post exposure hematology profile was observed to be normal. Clinical chemistry profile in all experimental groups are normal and within the physiological range. No significant changes were noticed in genotoxicity and cytotoxicity studies. The data demonstrated that the repeated administration of recombinant Exenedin-4 both subcutaneously did not exert any toxic effects on SD Rats at different dose levels until the end of the observation period. Recombinant Exenedin-4 was well tolerated upon subcutaneous administration to male and female SD Rats at various dosage levels. No adverse effects were detected at the highest dosage administrated. No treatment related changes were detected for body weight, feed intake, hematology, clinical chemistry, and organ weight. There were no adverse clinical signs indicative of an anaphylactic response. No significant changes in immunology profile such as antibody response and production of neutralizing antibodies were also not observed even at highest dose levels.
Keywords: Exendin-4, hematology, Clinical Chemistry, Genotoxicity, Cytotoxicity, Organ Weight.