Identification of the metabolites of ivermectin in humans

Abstract

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.

Sorption of selected antiparasitics in soils and sediments

“…For IVM, promising mass drug administrations to livestock to target malaria vectors [ 80 ] may increase drug release onto soils. If this approach is complemented with human IVM treatments [ 7 , 81 ], aquatic pathways in sewage systems could be subject to monitoring and analysis. This makes thorough drug exposure and fate assessments necessary.…”

“…If enough data is available, a multiple linear regression with all soil/sediment properties is always advisable. Also, while for IVM low metabolization has been described in animal species [ 14 ], human metabolism of IVM could be more pronounced [ 81 ]. Transformation products of varying size and polarity could hypothetically demonstrate different sorption behavior in soils and sediments.…”

Ivermectin: A Promising Therapeutic for Fighting Malaria. Current Status and Perspective

“…While the mean peak plasma concentration of these metabolites was 2.5-fold higher than that of 2 , the effective half-lives were approximately 6.0-fold longer compared with 2 . Recently, 13 different metabolites were identified by different methods, including incubation of 2 with (i) human liver microsomes and (ii) human hepatocytes and (iii) from human volunteers treated with 2 (1 × 400 μg/kg). The structures of two metabolites, 20 and 21 (Figure ), were characterized using NMR spectroscopy and high-resolution mass spectrometry.…”

“…Structures of 20 and 21 , which are metabolites of 2 . The biotransformation sites are highlighted in red shading …”

Forest malaria and prospects for anti-malarial chemoprophylaxis among forest goers: findings from a qualitative study in Thailand

“…To accelerate elimination, mass drug administration (MDA) has recently been implemented in areas where transmission is low [ 12 – 14 ]. Seasonal malaria chemoprevention (SMC) has been used in seasonal-transmission settings [ 15 ] and intermittent preventive treatment (IPT) [ 16 ] has been administered to pregnant women [ 17 ], infants and children in endemic areas [ 18 , 19 ]. Chemoprophylaxis is often provided to travellers and military personnel visiting transmission areas [ 20 ].…”