Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes
Abstract Background Ivermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated wi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Malaria Journal |
| Online Access: | https://doi.org/10.1186/s12936-023-04624-0 |
| _version_ | 1827917145178112000 |
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| author | Charlotte Kern Pie Müller Carlos Chaccour Matthias E. Liechti Felix Hammann Urs Duthaler |
| author_facet | Charlotte Kern Pie Müller Carlos Chaccour Matthias E. Liechti Felix Hammann Urs Duthaler |
| author_sort | Charlotte Kern |
| collection | DOAJ |
| description | Abstract Background Ivermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A “post-ivermectin effect” has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect. Methods Ivermectin was incubated in the presence of recombinant human cytochrome P450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (Cmax) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days. Results Human CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1–M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H2B1a) was mainly produced by CYP3A5. Both desmethyl-H2B1a (M1) and hydroxy-H2B1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H2B1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at Cmax levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h). Conclusion In conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the “post-ivermectin effect”. |
| first_indexed | 2024-03-13T03:24:40Z |
| format | Article |
| id | doaj.art-d7ca8cf4767c49129b8d740a887b535c |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-03-13T03:24:40Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-d7ca8cf4767c49129b8d740a887b535c2023-06-25T11:09:39ZengBMCMalaria Journal1475-28752023-06-0122111710.1186/s12936-023-04624-0Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoesCharlotte Kern0Pie Müller1Carlos Chaccour2Matthias E. Liechti3Felix Hammann4Urs Duthaler5Division of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital BernSwiss Tropical and Public Health InstituteISGlobal, Hospital Clínic - Universitat de BarcelonaDivision of Clinical Pharmacology & Toxicology, Department of Biomedicine, University and University Hospital BaselDivision of Clinical Pharmacology & Toxicology, Department of Internal Medicine, University Hospital BernDivision of Clinical Pharmacology & Toxicology, Department of Biomedicine, University and University Hospital BaselAbstract Background Ivermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A “post-ivermectin effect” has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect. Methods Ivermectin was incubated in the presence of recombinant human cytochrome P450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (Cmax) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days. Results Human CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1–M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H2B1a) was mainly produced by CYP3A5. Both desmethyl-H2B1a (M1) and hydroxy-H2B1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H2B1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at Cmax levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h). Conclusion In conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the “post-ivermectin effect”.https://doi.org/10.1186/s12936-023-04624-0 |
| spellingShingle | Charlotte Kern Pie Müller Carlos Chaccour Matthias E. Liechti Felix Hammann Urs Duthaler Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes Malaria Journal |
| title | Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes |
| title_full | Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes |
| title_fullStr | Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes |
| title_full_unstemmed | Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes |
| title_short | Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes |
| title_sort | pharmacokinetics of ivermectin metabolites and their activity against anopheles stephensi mosquitoes |
| url | https://doi.org/10.1186/s12936-023-04624-0 |
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