The pharmacokinetics and metabolism of ivermectin in domestic animal species

Canga, Aránzazu González; Sahagún, Ana M.; Diez, M. José; Martínez, Nélida Fernández; Sierra, Matilde; Vieitez, Juan José García

doi:10.1016/j.tvjl.2007.07.011

Cited by 208 publications

(144 citation statements)

References 47 publications

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“…This program calculated noncompartmental parameters using the statistical moment theory (Gibaldi and Perrier 1982;Martinez 1998). The C max (maximum serum concentration) and T max (time of maximum serum concentration) were taken directly from the curve.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

et al. 2008

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This study investigated the comparative serum disposition kinetics of ivermectin (IVM) after a single subcutaneous dose of 200 microg/kg body weight of IVM alone or in combination with an anthelmintic consisting of ivermectin and rafoxanide (200 microg/kg of IVM and 2.5 mg/kg rafoxanide) for use in calves and sheep. The IVM concentrations in serum samples were analyzed by high-performance liquid chromatography with fluorescence detection. In sheep serum, rafoxanide induced a rapid absorption of IVM when given in combined form manifested by a shorter absorption half-life time of IVM by 68.49% when given in combination as compared with IVM when given alone. In addition, there is an increase in the value of the area under the concentration curve (AUC) by 15.48% while the value of elimination rate constant was decreased by 38.2% and significantly increased the half-life time of elimination from 2.04 days for IVM alone to 3.3 days when given in combination with rafoxanide. In calves serum, the mean t1/2ab for IVM/rafoxanide was 0.131 days and for the control formulation 0.16 days, and t1/2el was 5.78 and 4.95, respectively. IVM Cmax for IVM/rafoxanide was 22.4 ng/ml and for the control formulation 19.1 ng/ml. T (max) values were 0.99 and 1.12 days, and the mean AUC values were 188.9 and 165.4 ng/ml/day. The difference in Cmax, AUC, Kab, K el, and t1/2el was significant. However, there was no statistical difference between the Tmax and t1/2ab. These findings revealed that the combination of rafoxanide with IVM in sheep and calves increased the absorption of IVM and delayed its elimination.

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Section: Pharmacokinetic Analysismentioning

confidence: 99%

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

et al. 2008

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“…Campbell and Omura (12), and implicated as an efficient agent against parasites, which earned a Nobel Prize for physiology or medicine in 2015. Subsequently, ivermectin, an avermectin derivative, was chemically modified and found to be a more effective compound against a variety of parasites (13). Recently, ivermectin has been identified as a promising anticancer agent for colon cancer, ovarian cancer, melanoma, and leukemia (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

et al. 2016

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Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitinationmediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457-69. Ó2016 AACR.

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“…There are also a growing number of studies on the metabolism of pharmaceuticals in fish [30][31][32][33][34][35][36][37][38][39][40] and to a far lesser extent invertebrates [41]. Veterinary pharmaceuticals have also been studied from a comparative metabolism perspective [42,43]. Table 1 …”

Section: Introductionmentioning

confidence: 99%

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Hutchinson

Madden

Naidoo

et al. 2014

Phil. Trans. R. Soc. B

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Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment.

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The pharmacokinetics and metabolism of ivermectin in domestic animal species

Cited by 208 publications

References 47 publications

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

Comparative pharmacokinetics of ivermectin alone and a novel formulation of ivermectin and rafoxanide in calves and sheep

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

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