Comparative in Vivoand in Vitro Metabolism of Ivermectin in Steers, Sheep, Swine, and Rat

Chiu, Shuet‐Hing Lee; Taub, Rae; Sestokas, E.; Lu, Anthony Y. H.; Jacob, Theodore A.

doi:10.3109/03602538708998309

Cited by 45 publications

(8 citation statements)

References 10 publications

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“…Previous animal studies suggest dual CYP3A4/P-gp inhibitors do not significantly modify the PK of one of the major ivermectin metabolites, 3 O-desmethyl ivermectin 35 , 36 potentially suggesting an increase in systemic exposure mostly due to reduced excretion rather than reduced metabolism. Nonetheless, the evaluation of ivermectin metabolites is a complex process 22 , 67 and their potential role in the insecticidal effect of the drug would require additional investments.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Chaccour

Hammann

Alustiza

et al. 2017

Sci Rep

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Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Chaccour

Hammann

Alustiza

et al. 2017

Sci Rep

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“…Authors have resorted to first identify metabolites in vitro by means of liver microsomes before attempting an in vivo characterization [27, 35]. The correlation of both systems is good in several species tested.…”

Section: Essential Pharmacologymentioning

confidence: 99%

“…The correlation of both systems is good in several species tested. Following this methodology, three polar metabolites: 24-hydroxymethyl-H 2 B 1a , 24-hydroxymethyl-H 2 B 1a -Monosaccharide and 24-hydroxymethyl-H 2 B 1b account for up to 50% of all metabolites in liver tissue of cattle, rat and sheep in the first 14 days after dosing [27, 35]. In swine, more than two-thirds of liver residues are composed of 3″- O -desmethyl-H 2 B 1a and 3″- O -desmethyl- H 2 B 1b [27, 35].…”

Section: Essential Pharmacologymentioning

confidence: 99%

Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety

Chaccour

Hammann

Rabinovich

2017

Malar J

105

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Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1801-4) contains supplementary material, which is available to authorized users.

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“…Investigating IVM metabolite formation in mammalian liver microsomes has already elucidated the contribution of human Cyp isoforms to IVM metabolism, particularly cytochrome P450 3A4 [ 29 , 30 , 31 ]. Inhibition of human liver-derived Cyp-3A4 with troleandomycin specifically diminished IVM biotransformation by >90, thereby revealing Cyp-3A4 as a critical enzyme in IVM biotransformation [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Transgenic Expression of Haemonchus contortus Cytochrome P450 Hco-cyp-13A11 Decreases Susceptibility to Particular but Not All Macrocyclic Lactones in the Model Organism Caenorhabditis elegans

Jakobs

Yilmaz

Krücken

2022

IJMS

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The number of reported macrocyclic lactones (ML) resistance cases across all livestock hosts is steadily increasing. Different studies in the parasitic nematode Haemonchus contortus assume the participation of cytochrome P450s (Cyps) enzymes in ML resistance. Still, functional data about their individual contribution to resistance or substrate specificity is missing. Via microinjection, transgenic Caenorhabditis elegans expressing HCON_00141052 (transgene-Hco-cyp-13A11) from extrachromosomal arrays were generated. After 24 h of exposure to different concentrations of ivermectin (IVM), ivermectin aglycone (IVMa), selamectin (SEL), doramectin (DRM), eprinomectin (EPR), and moxidectin (MOX), motility assays were performed to determine the impact of the H. contortus Cyp to the susceptibility of the worms against each ML. While transgene-Hco-cyp-13A11 significantly decreased susceptibility to IVM (four-fold), IVMa (2-fold), and SEL (3-fold), a slight effect for DRM and no effect for MOX, and EPR was observed. This substrate specificity of Hco-cyp-13A11 could not be explained by molecular modeling and docking studies. Hco-Cyp-13A11 molecular models were obtained for alleles from isolates with different resistance statuses. Although 14 amino acid polymorphisms were detected, none was resistance specific. In conclusion, Hco-cyp-13A11 decreased IVM, IVMa, and SEL susceptibility to a different extent, but its potential impact on ML resistance is not driven by polymorphisms.

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Comparative in Vivoand in Vitro Metabolism of Ivermectin in Steers, Sheep, Swine, and Rat

Cited by 45 publications

References 10 publications

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae

Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety

Transgenic Expression of Haemonchus contortus Cytochrome P450 Hco-cyp-13A11 Decreases Susceptibility to Particular but Not All Macrocyclic Lactones in the Model Organism Caenorhabditis elegans

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