Ivermectin and Abamectin Metabolism

Halley, Bruce A.; Narasimhan, Narayana I.; Venkataraman, Kalpana; Taub, Rae; Erwin, Marilyn L. G.; Andrew, N. W.; Wislocki, Peter G.

doi:10.1021/bk-1992-0503.ch014

Cited by 6 publications

(6 citation statements)

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“…Within ERAPharm, 2 potential metabolites of ivermectin were identified in cattle dung: 24‐hydroxymethyl‐H 2 B 1a and 3′′‐ O ‐desmethyl‐H 2 B 1a (Pope 2010). These metabolites were also reported to be the most prominent in cattle and swine liver (Chiu et al 1986, 1990; Halley et al 1992). However, the potential metabolites could not be quantified because of time constraints on the preparation of the appropriate metabolite standards.…”

Section: Phase II Tier Amentioning

confidence: 94%

Environmental risk assessment of ivermectin: A case study

Liebig¹,

Alonso²,

Blübaum-Gronau³

et al. 2010

Integr Envir Assess & Manag

133

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The veterinary parasiticide ivermectin was selected as a case study compound within the project ERAPharm (Environmental Risk Assessment of Pharmaceuticals). Based on experimental data generated within ERAPharm and additional literature data, an environmental risk assessment (ERA) was performed mainly according to international and European guidelines. For the environmental compartments surface water, sediment, and dung, a risk was indicated at all levels of the tiered assessment approach. Only for soil was no risk indicated after the lower tier assessment. However, the use of effects data from additional 2-species and multispecies studies resulted in a risk indication for collembolans. Although previously performed ERAs for ivermectin revealed no concern for the aquatic compartment, and transient effects on dung-insect populations were not considered as relevant, the present ERA clearly demonstrates unacceptable risks for all investigated environmental compartments and hence suggests the necessity of reassessing ivermectin-containing products. Based on this case study, several gaps in the existing guidelines for ERA of pharmaceuticals were shown and improvements have been suggested. The action limit at the start of the ERA, for example, is not protective for substances such as ivermectin when used on intensively reared animals. Furthermore, initial predicted environmental concentrations (PECs) of ivermectin in soil were estimated to be lower than refined PECs, indicating that the currently used tiered approach for exposure assessment is not appropriate for substances with potential for accumulation in soil. In addition, guidance is lacking for the assessment of effects at higher tiers of the ERA, e.g., for field studies or a tiered effects assessment in the dung compartment.

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Section: Phase II Tier Amentioning

confidence: 94%

Environmental risk assessment of ivermectin: A case study

Liebig¹,

Alonso²,

Blübaum-Gronau³

et al. 2010

Integr Envir Assess & Manag

133

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“…SEL, in addition to having a saturated spiroketal moiety that is similar to IVM, also has a cyclohexyl ring in place of the isopropyl/isobutyl substituent on IVM and ABM. The absence of the C22-C23 double bond in IVM alters the conformation of the spiroketal moiety and modifies its metabolism in comparison with ABM (Halley et al, 1992). However, given the comparable ability of both IVM and ABM to antagonize the inhibitory effects of ethanol in P2X4Rs more effectively than SEL, it seems that their spiroketal differences are not the primary determinant for this effect.…”

Section: Discussionmentioning

confidence: 99%

Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders

Asatryan¹,

Yardley

Khoja

et al. 2014

Int. J. Neuropsychopharm.

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Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Prior work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM’s ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM’s effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy. We tested this hypothesis by comparing the abilities of IVM and two other avermectins, abamectin (ABM) and selamectin (SEL), to reduce ethanol intake in mice, to alter modulation of GABA ARs and P2X4Rs expressed in Xenopus oocytes and to increase their ability to penetrate the brain. IVM and ABM significantly reduced ethanol intake and antagonized the inhibitory effects of ethanol on P2X4R function. In contrast, SEL did not affect either measure, despite achieving higher brain concentrations than IVM and ABM. All three potentiated GABAA receptor function. These findings suggest that chemical structure and effects on receptor function play key roles in the ability of avermectins to reduce ethanol intake and that these factors are more important than brain penetration alone. The direct relationship between the effect of these avermectins on P2X4R function and ethanol intake suggest that the ability to antagonize ethanol-mediated inhibition of P2X4R function may be a good predictor of the potential of an avermectin to reduce ethanol intake and support the use of avermectins as a platform for developing novel drugs to prevent and/or treat AUDs.

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“…10,11 The LC 50 of AVM at 96 h was 3.2 μg L −1 for rainbow trout, 9.6 μg L −1 for bluegill sunfish, 15 μg L −1 for sheepshead minnow, 24 μg L −1 for channel catfish and 42 μg L −1 for carp. 10,11 The LC 50 of AVM at 96 h was 3.2 μg L −1 for rainbow trout, 9.6 μg L −1 for bluegill sunfish, 15 μg L −1 for sheepshead minnow, 24 μg L −1 for channel catfish and 42 μg L −1 for carp.…”

Section: Dose Finding Experimentsmentioning

confidence: 98%

“…The experimental dose and exposure time were determined in our initial experiments in full consideration of the reported toxicity data of AVM in various species. 10,11 The LC 50 of AVM at 96 h was 3.2 μg L −1 for rainbow trout, 9.6 μg L −1 for bluegill sunfish, 15 μg L −1 for sheepshead minnow, 24 μg L −1 for channel catfish and 42 μg L −1 for carp. However, no toxic data were available for AVM on goldfish.…”

Section: Dose Finding Experimentsmentioning

confidence: 98%

Insight into biological system responses in goldfish (Carassius auratus) to multiple doses of avermectin exposure by integrated¹H NMR-based metabolomics

Ruan

Liu

et al. 2015

Toxicol. Res.

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The toxic effects of AVM were investigated using a teleost experimental model, the juvenile goldfish (Carassius auratus). Goldfish were consecutively exposed to AVM for 7 days and then the tissues of brains, kidneys and livers and plasma were collected and subjected to a NMR based metabolomics study. AVM changed the metabolomic profiles of goldfish dose-dependently and significantly changed the levels of metabolites in dosed goldfish, such as the branch-chain amino acids (BCAAs), aromatic amino acids (AAAs), betaine, taurine, lactate, etc. These metabolite changes affect energy metabolism, amino acid metabolism, nucleic acids metabolism, osmotic equilibrium as well as redox equilibrium, and are related with the toxicity of AVM. 1 H NMR-based metabolomics approach promises to be an advantageous tool for the systematic and holistic view of the response of aquatic organisms to pesticides and is thus suitable for the assessment of the environmental risk of pesticides and the understanding of the underlying mechanism. Fig. 1 Chemical structures of AVM. † Electronic supplementary information (ESI) available. See

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Ivermectin and Abamectin Metabolism

Cited by 6 publications

References 0 publications

Environmental risk assessment of ivermectin: A case study

Environmental risk assessment of ivermectin: A case study

Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders

Insight into biological system responses in goldfish (Carassius auratus) to multiple doses of avermectin exposure by integrated¹H NMR-based metabolomics

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Ivermectin and Abamectin Metabolism

Cited by 6 publications

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Environmental risk assessment of ivermectin: A case study

Environmental risk assessment of ivermectin: A case study

Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders

Insight into biological system responses in goldfish (Carassius auratus) to multiple doses of avermectin exposure by integrated1H NMR-based metabolomics

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Insight into biological system responses in goldfish (Carassius auratus) to multiple doses of avermectin exposure by integrated¹H NMR-based metabolomics