High doses of ivermectin cause toxic effects after shortterm oral administration in rats

Marjanović, Vladimir (author), Medić, Dragana (author), Marjanović, Djordje S. (author), Andrić, Nenad (author), Petrović, Miloš Ž. (author), Andrić, Jelena Francuski (author), Radaković, Milena (author), Krstić, Vanja (author), Trailović, Saša (author)

The anthelmintic macrocyclic lactones (MLs) are the most important endec-tocides in modern pharmacotherapy of parasitic infections. However, during the COVID 19 pandemic, ivermectin was used in humans against infection with the SARS-CoV-2 virus in doses significantly higher than the approved antiparasitic doses. This kind of ap-plication was created solely on the basis of in vitro tests, and is not officially approved in any country in the world. Therefore, we conducted a study on rats treated orally with 0.6, 1.2, 2.4 and 4.8 mg/kg of ivermectin for 5 days. Based on our investigation, ivermectin at the doses used in humans against the SARS-Co-2 virus (3, 6, 12 and 24 times higher than the antiparasitic dose 0.2mg/kg), causes changes in red blood cell counts and in-creases the levels of liver enzymes without visible clinical symptoms. Histopathological changes were recorded in the liver, kidneys and testicles of rats, and the highest dose tested led to bleeding in the brain tissue. Obviously, ivermectin somewhat increases concentration of the enzyme P-450 isoform 3A4, whose substrate it is, but the high-est tested dose reduces its concentration in plasma to the control level. Notably, the concentrations of ivermectin recorded in plasma of treated rats, indicate that even high doses do not reach the in vitro IC50 value of ivermectin for SARS-CoV-2 reported in the literature. On the other hand, the concentrations of ivermectin in the brain approach the values that can manifest extremely toxic effects described in humans.

• Language: English
• Keywords: ivermectin, toxicity, SARS-CoV-2, cytochrome P-450, P-gp, histopathological changes, rats
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: VF - Veterinary Faculty
• Publication status: Published
• Publication version: Version of Record
• Publication date: 01.01.2024
• Year: 2024
• Number of pages: Str. 281-290
• Numbering: Vol. 61, no. 4
• PID: 20.500.12556/RUL-168103
• UDC: 599.323.55:612.014.43:615.2:616.24-002:631.816.1
• ISSN on article: 1580-4003
• DOI: 10.26873/SVR-2069-2024
• COBISS.SI-ID: 227468547
• Publication date in RUL: 28.03.2025

Record is a part of a journal

• Title: Slovenian veterinary research : the scientific journal of the Veterinary Faculty University of Ljubljana
• Shortened title: Slov. vet. res.
• Publisher: Veterinarska fakulteta, Veterinarska fakulteta, Založba Univerze v Ljubljani
• ISSN: 1580-4003
• COBISS.SI-ID: 108028416

Secondary language

• Language: Slovenian
• Title: Veliki odmerki ivermektina povzročajo toksične učinke pri podganah pokratkotrajnem peroralnem dajanju

Projects

• Funder: MESTD - Ministry of Education, Science and Technological Development of Republic of Serbia
• Project number: 451-03-47/2023-01/200143

• Funder: Science Found of the Republic of Serbia
• Project number: 7355
• Name: FARMACASA