Identification of the metabolites of ivermectin in humans
Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and...
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th-mahidol.789032022-08-04T18:23:15Z Identification of the metabolites of ivermectin in humans Phornpimon Tipthara Kevin C. Kobylinski Markus Godejohann Borimas Hanboonkunupakarn Alison Roth John H. Adams Nicholas J. White Podjanee Jittamala Nicholas P.J. Day Joel Tarning Bruker BioSpin GmbH, Germany University of South Florida Health Armed Forces Research Institute of Medical Sciences, Thailand Walter Reed Army Institute of Research Mahidol University Nuffield Department of Medicine Neuroscience Pharmacology, Toxicology and Pharmaceutics Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites. 2022-08-04T11:15:52Z 2022-08-04T11:15:52Z 2021-02-01 Article Pharmacology Research and Perspectives. Vol.9, No.1 (2021) 10.1002/prp2.712 20521707 2-s2.0-85100498236 https://repository.li.mahidol.ac.th/handle/123456789/78903 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85100498236&origin=inward |
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Neuroscience Pharmacology, Toxicology and Pharmaceutics Phornpimon Tipthara Kevin C. Kobylinski Markus Godejohann Borimas Hanboonkunupakarn Alison Roth John H. Adams Nicholas J. White Podjanee Jittamala Nicholas P.J. Day Joel Tarning Identification of the metabolites of ivermectin in humans |
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Mass drug administration of ivermectin has been proposed as a possible malaria elimination tool. Ivermectin exhibits a mosquito-lethal effect well beyond its biological half-life, suggesting the presence of active slowly eliminated metabolites. Human liver microsomes, primary human hepatocytes, and whole blood from healthy volunteers given oral ivermectin were used to identify ivermectin metabolites by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. The molecular structures of metabolites were determined by mass spectrometry and verified by nuclear magnetic resonance. Pure cytochrome P450 enzyme isoforms were used to elucidate the metabolic pathways. Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the major metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure, defined by LC-MS/MS and NMR, indicated that M1 is 3″-O-demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O-demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1, M3, and M6 were produced primarily by CYP3A4, and that M1 was also produced to a small extent by CYP3A5. Demethylated (M1) and hydroxylated (M3) ivermectin were the main human in vivo metabolites. Further studies are needed to characterize the pharmacokinetic properties and mosquito-lethal activity of these metabolites. |
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Bruker BioSpin GmbH, Germany |
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Bruker BioSpin GmbH, Germany Phornpimon Tipthara Kevin C. Kobylinski Markus Godejohann Borimas Hanboonkunupakarn Alison Roth John H. Adams Nicholas J. White Podjanee Jittamala Nicholas P.J. Day Joel Tarning |
format |
Article |
author |
Phornpimon Tipthara Kevin C. Kobylinski Markus Godejohann Borimas Hanboonkunupakarn Alison Roth John H. Adams Nicholas J. White Podjanee Jittamala Nicholas P.J. Day Joel Tarning |
author_sort |
Phornpimon Tipthara |
title |
Identification of the metabolites of ivermectin in humans |
title_short |
Identification of the metabolites of ivermectin in humans |
title_full |
Identification of the metabolites of ivermectin in humans |
title_fullStr |
Identification of the metabolites of ivermectin in humans |
title_full_unstemmed |
Identification of the metabolites of ivermectin in humans |
title_sort |
identification of the metabolites of ivermectin in humans |
publishDate |
2022 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/78903 |
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1763489669871304704 |