Efficacy of ivermectin and its metabolites against Plasmodium falciparum liver stages in primary human hepatocytes.

Autor: Annamalai Subramani P; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA., Tipthara P; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand., Kolli SK; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA., Nicholas J; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA., Barnes SJ; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA., Ogbondah MM; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA., Kobylinski KC; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand., Tarning J; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom., Adams JH; Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Aug 07; Vol. 68 (8), pp. e0127223. Date of Electronic Publication: 2024 Jun 21.
DOI: 10.1128/aac.01272-23
Abstrakt: Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing Anopheles mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on Plasmodium liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3″- O -demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against Plasmodium falciparum liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0-3 post-infection) and curative mode (days 3-5 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC 50 ) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC 50 values ranging from 1.391 to 14.44, 9.95-23.71, 4.767-8.384, and 0.9073-5.416 µM, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against P. falciparum liver stages in curative treatment mode (days 3-5) and marginal activity in prophylactic treatment mode (days 0-3). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites in vitro .
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
Externí odkaz: