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Ichinose P, Miró MV, Larsen K, Lifschitz A, Virkel G. Unravelling drug-drug interactions in pigs: Induction of hepatic cytochrome P450 1A (CYP1A) metabolism after the in-feed medication with the anthelmintic fenbendazole. Res Vet Sci 2024; 167:105113. [PMID: 38141570 DOI: 10.1016/j.rvsc.2023.105113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/25/2023]
Abstract
The anthelmintic fenbendazole (FBZ) undergoes hepatic S‑oxygenation by monooxygenases belonging to the cytochrome P450 (CYP) and flavin-monooxygenase (FMO) families. The in-feed medication with FBZ induced CYP1A-dependent metabolism in pig liver. This fact may alter the metabolism of the anthelmintic itself, and of CYP1A substrates like aflatoxin B1 (AFB1). This work evaluated the effect of the in-feed administration of FBZ on CYP1A-dependent metabolism, on its own pattern of hepatic S‑oxygenation, and on the metabolism of AFB1. Landrace piglets remained untreated (n = 5) or received a pre-mix of FBZ (n = 6) in feed for 9 days. Pigs were slaughtered for preparation of liver microsomes used for: CYP content determination; monitoring the CYP1A-dependent enzyme activities, 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD); measurement of FBZ (50 μM) S‑oxygenation, and AFB1 (16 nM) disappearance from the incubation medium. In microsomes of FBZ-treated animals, EROD and MROD increased 19-fold (p = 0.002) and 14-fold (p = 0.003), respectively. An enhanced (3-fold, p = 0.004) participation of the CYP pathway in FBZ S‑oxygenation was observed in the liver of piglets treated with the anthelmintic (210 ± 69 pmol/min.nmol CYP) compared to untreated animals (68 ± 34 pmol/min.nmol CYP). AFB1 metabolism was 93% higher (p = 0.009) in the liver of FBZ-treated compared to untreated pigs. Positive and significant (p < 0.05) correlations were observed between CYP1A-dependent enzyme activities and FBZ or AFB1 metabolism. The sustained administration of FBZ caused an auto-induction of the CYP1A-dependent S‑oxygenation of this anthelmintic. The CYP1A induction triggered by the anthelmintic could amplify the production of AFB1 metabolites in pig liver, including the hepatotoxic AFB1-derived epoxide.+.
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Affiliation(s)
- Paula Ichinose
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, Buenos Aires, Argentina
| | - María Victoria Miró
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, Buenos Aires, Argentina
| | - Karen Larsen
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, Buenos Aires, Argentina
| | - Adrián Lifschitz
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, Buenos Aires, Argentina
| | - Guillermo Virkel
- Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Facultad de Ciencias Veterinarias, Tandil, Buenos Aires, Argentina; Centro de Investigación Veterinaria de Tandil (CIVETAN), UNCPBA-CICPBA-CONICET, Tandil, Buenos Aires, Argentina.
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Medication with fenbendazole in feed: plasma concentrations and effects on hepatic xenobiotic metabolizing enzymes in swine. Vet Res Commun 2022; 47:803-815. [PMID: 36542192 DOI: 10.1007/s11259-022-10041-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 11/18/2022] [Indexed: 12/24/2022]
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The Reduction of the Combined Effects of Aflatoxin and Ochratoxin A in Piglet Livers and Kidneys by Dietary Antioxidants. Toxins (Basel) 2021; 13:toxins13090648. [PMID: 34564652 PMCID: PMC8472784 DOI: 10.3390/toxins13090648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 11/25/2022] Open
Abstract
The purpose of this study was to investigate the combined effects of aflatoxin B1 and ochratoxin A on protein expression and catalytic activities of CYP1A2, CYP2E1, CYP3A29 and GSTA1 and the preventive effect of dietary byproduct antioxidants administration against these mycotoxin damage. Three experimental groups (E1, E2, E3) and one control group (C) of piglets after weaning (TOPIGS-40 hybrid) were fed with experimental diets for 30 days. A basal diet containing normal compound feed for starter piglets was used as a control treatment and free of mycotoxin. The experimental groups were fed as follows: E1—basal diet plus a mixture (1:1) of two byproducts (grapeseed and sea buckthorn meal), E2—the basal diet experimentally contaminated with mycotoxins (479 ppb OTA and 62ppb AFB1) and E3—basal diet containing 5% of the mixture (1:1) of grapeseed and sea buckthorn meal and contaminated with the mix of OTA and AFB1. After 4 weeks, the animals were slaughtered, and tissue samples were taken from liver and kidney in order to perform microsomal fraction isolation, followed by protein expression and enzymatic analyses. The protein expressions of CYP2E1 and CYP3A29 were up-regulated in an insignificant manner in liver, whereas in kidney, those of CYP1A2, CYP2E1 and CYP3A29 were down-regulated. The enzymatic activities of CYP1A2, CYP2E1 and CYP3A29 decreased in liver, in a significant manner, whereas in kidney, these increased significantly. The co-presence of the two mycotoxins and the mixture of grape seed and sea buckthorn meal generated a tendency to return to the control values, which suggest that grapeseed and sea buckthorn meal waste represent a promising source in counteracting the harmful effect of ochratoxin A and aflatoxin B.
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Eisemann JH, Ashwell MS, Devine TL, Poole DH, Poore MH, Linder KE. Physiological response, function of sweat glands, and hair follicle cycling in cattle in response to fescue toxicosis and hair genotype. J Anim Sci 2020; 98:5717958. [PMID: 31998943 DOI: 10.1093/jas/skaa013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 01/14/2020] [Indexed: 01/27/2023] Open
Abstract
Fescue toxicosis is a syndrome that results when cattle consume toxic endophyte-infected tall fescue. The objective of this study was to compare the response in physiological variables, sweat gland function, hair follicle cycling, and gene expression to feeding a total mixed ration that included tall fescue haylage and tall fescue seed containing a toxic endophyte (EI) or tall fescue haylage containing a nontoxic novel endophyte (EN) in beef heifers (Angus × Senepol heifers, n = 31) with 2 different hair genotypes. Numbers in each subgroup were as follows: novel endophyte, heterozygous slick (EN-S; n = 8), novel endophyte, homozygous hairy (wild type, EN-W; n = 7), endophyte-infected, heterozygous slick (EI-S; n = 10), and endophyte-infected, homozygous hairy (wild type, EI-W; n = 6). Physiological measurements were taken weekly for 7 wk. Data were analyzed using the MIXED procedure of SAS including dietary fescue treatment (EN vs. EI) and hair genotype (S vs. W) as main effects, day as a repeated measure, and temperature-humidity index (THI) as a covariate. Skin biopsies were taken before treatment initiation and on day 37 of treatment. Average surface temperature (ST) increased as the THI increased (P < 0.0001). Average ST was greater (P < 0.01) for animals fed EI than for animals fed the EN fescue diet, and greater (P < 0.01) for animals with the W genotype compared with animals with the S genotype. The difference between heifers with the S and W genotype was greater at greater THI (genotype × day interaction, P < 0.01). Transepidermal water loss (TEWL) was greater (P < 0.05) for animals with the S genotype compared with the W genotype and greater (P < 0.05) for heifers with the S genotype than for heifers with the W genotype when fed EI (36.7, 38.5, 30.0, and 38.7 g/m2 per hour for EN-W, EN-S, EI-W, and EI-S, respectively). The fraction of follicles in telogen in plucked hair samples for heifers fed EI was greater for animals with the S genotype than the W genotype (fraction in telogen: 0.456, 0.565, 0.297, 0.702 for EN-W, EN-S, EI-W, and EI-S, respectively; diet × genotype interaction, P < 0.05). Fraction of follicles in anagen was the opposite. EI fescue resulted in increased ST, changes in hair follicle cycling that support greater hair growth, and decreased TEWL for heifers with the W genotype compared with S genotype, suggesting greater heat stress in response to EI.
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Affiliation(s)
- Joan H Eisemann
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Melissa S Ashwell
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Thomas L Devine
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Daniel H Poole
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Matt H Poore
- Department of Animal Science, North Carolina State University, Raleigh, NC
| | - Keith E Linder
- Department of Population, Health and Pathobiology, North Carolina State University, Raleigh, NC
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Knych HK, Finno CJ, Baden R, Arthur RM, McKemie DS. Identification and characterization of the enzymes responsible for the metabolism of the non-steroidal anti-inflammatory drugs, flunixin meglumine and phenylbutazone, in horses. J Vet Pharmacol Ther 2020; 44:36-46. [PMID: 32757313 DOI: 10.1111/jvp.12891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 06/15/2020] [Accepted: 06/25/2020] [Indexed: 11/29/2022]
Abstract
The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug-drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450-mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma-hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5-OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5-OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug-drug interactions and identification of reasons for varying pharmacokinetics between horses.
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Affiliation(s)
- Heather K Knych
- K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.,Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Carrie J Finno
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Russell Baden
- K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA
| | - Rick M Arthur
- School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Daniel S McKemie
- K.L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA
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Kellerová P, Matoušková P, Lamka J, Vokřál I, Szotáková B, Zajíčková M, Pasák M, Skálová L. Ivermectin-induced changes in the expression of cytochromes P450 and efflux transporters in Haemonchus contortus female and male adults. Vet Parasitol 2019; 273:24-31. [DOI: 10.1016/j.vetpar.2019.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/12/2019] [Accepted: 07/20/2019] [Indexed: 12/12/2022]
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Virkel G, Ballent M, Lanusse C, Lifschitz A. Role of ABC Transporters in Veterinary Medicine: Pharmaco- Toxicological Implications. Curr Med Chem 2019; 26:1251-1269. [DOI: 10.2174/0929867325666180201094730] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 11/14/2017] [Accepted: 12/22/2017] [Indexed: 01/10/2023]
Abstract
Unlike physicians, veterinary practitioners must deal with a number of animal species with crucial differences in anatomy, physiology and metabolism. Accordingly, the pharmacokinetic behaviour, the clinical efficacy and the adverse or toxic effects of drugs may differ across domestic animals. Moreover, the use of drugs in food-producing species may impose a risk for humans due to the generation of chemical residues in edible products, a major concern for public health and consumer's safety. As is clearly known in human beings, the ATP binding cassette (ABC) of transport proteins may influence the bioavailability and elimination of numerous drugs and other xenobiotics in domestic animals as well. A number of drugs, currently available in the veterinary market, are substrates of one or more transporters. Therefore, significant drug-drug interactions among ABC substrates may have unpredictable pharmacotoxicological consequences in different species of veterinary interest. In this context, different investigations revealed the major relevance of P-gp and other transport proteins, like breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), in both companion and livestock animals. Undoubtedly, the discovery of the ABC transporters and the deep understanding of their physiological role in the different species introduced a new paradigm into the veterinary pharmacology. This review focuses on the expression and function of the major transport proteins expressed in species of veterinary interest, and their impact on drug disposition, efficacy and toxicity.
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Affiliation(s)
- Guillermo Virkel
- Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN-CONICETCICPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Campus Universitario (Los Ombues y Reforma Universitaria), (7000) Tandil, Prov. de Buenos Aires, Argentina
| | - Mariana Ballent
- Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN-CONICETCICPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Campus Universitario (Los Ombues y Reforma Universitaria), (7000) Tandil, Prov. de Buenos Aires, Argentina
| | - Carlos Lanusse
- Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN-CONICETCICPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Campus Universitario (Los Ombues y Reforma Universitaria), (7000) Tandil, Prov. de Buenos Aires, Argentina
| | - Adrián Lifschitz
- Laboratorio de Farmacologia, Centro de Investigacion Veterinaria de Tandil (CIVETAN-CONICETCICPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Campus Universitario (Los Ombues y Reforma Universitaria), (7000) Tandil, Prov. de Buenos Aires, Argentina
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Schoos A, Devreese M, Maes DG. Use of non-steroidal anti-inflammatory drugs in porcine health management. Vet Rec 2019; 185:172. [PMID: 31040220 DOI: 10.1136/vr.105170] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 03/29/2019] [Accepted: 04/09/2019] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Treatment of inflammation and pain management is an important topic in the welfare of pigs. It is very difficult for veterinary practitioners to choose the most appropriate product for a certain problem. This review aims to summarise and discuss the characteristics of different non-steroidal anti-inflammatory drugs (NSAIDs), as well as paracetamol and metamizole, available for pigs in the European Union. METHODS The databases Pubmed, Google Scholar, CliniPharm CliniTox and European Medicines Agency were searched. Relevant terms (eg,'meloxicam', 'fever', 'swine', 'pig', 'inflammation', 'castration', 'pain') were used to search for original articles, reviews and books. Only peer-reviewed articles were used. References from studies were also analysed in order to find additional relevant studies. CONCLUSION Studies which have investigated the efficacy of NSAIDs for different conditions, using different treatment regimens, are scarce. Most studies focused on the efficacy of NSAID-related pain alleviation in piglet castration, as well as the anti-inflammatory potential of NSAIDs in experimental inflammation models. Little research has been carried out on the use of metamizole, tolfenamic acid, paracetamol and sodium salicylate and their effect in pigs.
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Affiliation(s)
- Alexandra Schoos
- Ghent University, Faculty of Veterinary Medicine, Merelbeke, Belgium
| | - Mathias Devreese
- Ghent University, Faculty of Veterinary Medicine, Merelbeke, Belgium
| | - Dominiek Gd Maes
- Ghent University, Faculty of Veterinary Medicine, Merelbeke, Belgium
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Palócz O, Szita G, Csikó G. Alteration in Inflammatory Responses and Cytochrome P450 Expression of Porcine Jejunal Cells by Drinking Water Supplements. Mediators Inflamm 2019; 2019:5420381. [PMID: 30718974 PMCID: PMC6334367 DOI: 10.1155/2019/5420381] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/14/2018] [Accepted: 11/21/2018] [Indexed: 11/29/2022] Open
Abstract
The intestinal epithelium is the first determining barrier to the drugs administered per os. Cytochrome P450 (CYP) enzymes are substantial in the initial step of xenobiotic metabolism; therefore, intestinal CYP enzyme activities could be an important influencing factor of the oral utilization of xenobiotic substances. In this study, the effect of four drinking water supplements on CYP mRNA levels of porcine intestinal epithelial cells was examined. Further goal of the study is to describe the effect of these feed additives on the proinflammatory response of the LPS-treated enterocytes. The nontransformed porcine intestinal epithelial cells (IPEC-J2) were grown on six-well polyester membrane inserts. Cell cultures were treated with LPS (10 μg/ml), β-glucan (5 and 50 μg/ml), sanguinarine-containing additive (5 and 50 μg/ml), drinking water acidifier (0.1 and 1 μl/ml), and fulvic acid (25 and 250 μg/ml) for 1 hour. Cells were washed with culture medium and incubated for additional 1 h before total RNA isolation. IL-6, IL-8, TNF-α, HSP70, CYP1A1, CYP1A2, and CYP3A29 mRNA levels were measured. The LPS treatment upregulated the gene expression of IL-8 and TNF-α. The relative gene expression of IL-6 remained unchanged and TNF-α and HSP70 were downregulated after the treatment with each feed additive. CYP1A1 and CYP1A2 expressions increased after sanguinarine-containing solution, fulvic acid, and drinking water acidifier treatment. None of the treatments changed the gene expression of CYP3A29, responsible for the metabolism of the majority of drug substances used in swine industry. The feed additive substances inhibited the expression of proinflammatory mediators HSP70 and TNF-α; however, β-glucan and fulvic acid elevated the production of the chemokine IL-8 mRNA in endotoxin-treated enterocytes. All acidic supplements increased the expression of CYP1A1 gene; their constituents may serve as a ligand of CYP1A1 nuclear receptors.
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Affiliation(s)
- Orsolya Palócz
- Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2., Budapest 1078, Hungary
| | - Géza Szita
- Department of Food Hygiene, University of Veterinary Medicine, István u. 2, Budapest 1078, Hungary
| | - György Csikó
- Department of Pharmacology and Toxicology, University of Veterinary Medicine, István u. 2., Budapest 1078, Hungary
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Howard JT, Ashwell MS, Baynes RE, Brooks JD, Yeatts JL, Maltecca C. Genetic Parameter Estimates for Metabolizing Two Common Pharmaceuticals in Swine. Front Genet 2018; 9:40. [PMID: 29487615 PMCID: PMC5816749 DOI: 10.3389/fgene.2018.00040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 01/29/2018] [Indexed: 11/13/2022] Open
Abstract
In livestock, the regulation of drugs used to treat livestock has received increased attention and it is currently unknown how much of the phenotypic variation in drug metabolism is due to the genetics of an animal. Therefore, the objective of the study was to determine the amount of phenotypic variation in fenbendazole and flunixin meglumine drug metabolism due to genetics. The population consisted of crossbred female and castrated male nursery pigs (n = 198) that were sired by boars represented by four breeds. The animals were spread across nine batches. Drugs were administered intravenously and blood collected a minimum of 10 times over a 48 h period. Genetic parameters for the parent drug and metabolite concentration within each drug were estimated based on pharmacokinetics (PK) parameters or concentrations across time utilizing a random regression model. The PK parameters were estimated using a non-compartmental analysis. The PK model included fixed effects of sex and breed of sire along with random sire and batch effects. The random regression model utilized Legendre polynomials and included a fixed population concentration curve, sex, and breed of sire effects along with a random sire deviation from the population curve and batch effect. The sire effect included the intercept for all models except for the fenbendazole metabolite (i.e., intercept and slope). The mean heritability across PK parameters for the fenbendazole and flunixin meglumine parent drug (metabolite) was 0.15 (0.18) and 0.31 (0.40), respectively. For the parent drug (metabolite), the mean heritability across time was 0.27 (0.60) and 0.14 (0.44) for fenbendazole and flunixin meglumine, respectively. The errors surrounding the heritability estimates for the random regression model were smaller compared to estimates obtained from PK parameters. Across both the PK and plasma drug concentration across model, a moderate heritability was estimated. The model that utilized the plasma drug concentration across time resulted in estimates with a smaller standard error compared to models that utilized PK parameters. The current study found a low to moderate proportion of the phenotypic variation in metabolizing fenbendazole and flunixin meglumine that was explained by genetics in the current study.
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Affiliation(s)
- Jeremy T Howard
- Department of Animal Science, North Carolina State University, Raleigh, NC, United States
| | - Melissa S Ashwell
- Department of Animal Science, North Carolina State University, Raleigh, NC, United States
| | - Ronald E Baynes
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, United States
| | - James D Brooks
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, United States
| | - James L Yeatts
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, United States
| | - Christian Maltecca
- Department of Animal Science, North Carolina State University, Raleigh, NC, United States
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Metabolism of albendazole, ricobendazole and flubendazole in Haemonchus contortus adults: Sex differences, resistance-related differences and the identification of new metabolites. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE 2018; 8:50-58. [PMID: 29414106 PMCID: PMC6114105 DOI: 10.1016/j.ijpddr.2018.01.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 12/22/2022]
Abstract
Haemonchus contortus (family Trichostrongylidae, Nematoda), a hematophagous gastrointestinal parasite found in small ruminants, has a great ability to develop resistance to anthelmintic drugs. We studied the biotransformation of the three benzimidazole anthelmintics: albendazole (ABZ), ricobendazole (albendazole S-oxide; RCB) and flubendazole (FLU) in females and males of H. contortus in both a susceptible ISE strain and resistant IRE strain. The ex vivo cultivation of living nematodes in culture medium with or without the anthelmintics was used. Ultrasensitive UHPLC/MS/MS analysis revealed 9, 7 and 12 metabolites of ABZ, RCB and FLU, respectively, with most of these metabolites now described in the present study for the first time in H. contortus. The structure of certain metabolites shows the presence of biotransformation reactions not previously reported in nematodes. There were significant qualitative and semi-quantitative differences in the metabolites formed by male and female worms. In most cases, females metabolized drugs more extensively than males. Adults of the IRE strain were able to form many more metabolites of all the drugs than adults of the ISE strain. Some metabolites were even found only in adults of the IRE strain. These findings suggest that increased drug metabolism may play a role in resistance to benzimidazole drugs in H. contortus.
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Howard JT, Ashwell MS, Baynes RE, Brooks JD, Yeatts JL, Maltecca C. Gene co-expression network analysis identifies porcine genes associated with variation in metabolizing fenbendazole and flunixin meglumine in the liver. Sci Rep 2017; 7:1357. [PMID: 28465592 PMCID: PMC5430975 DOI: 10.1038/s41598-017-01526-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 03/29/2017] [Indexed: 12/31/2022] Open
Abstract
Identifying individual genetic variation in drug metabolism pathways is of importance not only in livestock, but also in humans in order to provide the ultimate goal of giving the right drug at the right dose at the right time. Our objective was to identify individual genes and gene networks involved in metabolizing fenbendazole (FBZ) and flunixin meglumine (FLU) in swine liver. The population consisted of female and castrated male pigs that were sired by boars represented by 4 breeds. Progeny were randomly placed into groups: no drug (UNT), FLU or FBZ administered. Liver transcriptome profiles from 60 animals with extreme (i.e. fast or slow drug metabolism) pharmacokinetic (PK) profiles were generated from RNA sequencing. Multiple cytochrome P450 (CYP1A1, CYP2A19 and CYP2C36) genes displayed different transcript levels across treated versus UNT. Weighted gene co-expression network analysis identified 5 and 3 modules of genes correlated with PK parameters and a portion of these were enriched for biological processes relevant to drug metabolism for FBZ and FLU, respectively. Genes within identified modules were shown to have a higher transcript level relationship (i.e. connectivity) in treated versus UNT animals. Investigation into the identified genes would allow for greater insight into FBZ and FLU metabolism.
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Affiliation(s)
- Jeremy T Howard
- Department of Animal Science, North Carolina State University, Raleigh, NC 27695-7621, USA
| | - Melissa S Ashwell
- Department of Animal Science, North Carolina State University, Raleigh, NC 27695-7621, USA
| | - Ronald E Baynes
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Road, Raleigh, North Carolina, 27606, USA
| | - James D Brooks
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Road, Raleigh, North Carolina, 27606, USA
| | - James L Yeatts
- Department of Population Health and Pathobiology, Center for Chemical Toxicology and Research Pharmacokinetics, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Road, Raleigh, North Carolina, 27606, USA
| | - Christian Maltecca
- Department of Animal Science, North Carolina State University, Raleigh, NC 27695-7621, USA.
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13
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Kasimanickam V, Kastelic J. MicroRNA in sperm from Duroc, Landrace and Yorkshire boars. Sci Rep 2016; 6:32954. [PMID: 27597569 PMCID: PMC5011730 DOI: 10.1038/srep32954] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 08/17/2016] [Indexed: 12/12/2022] Open
Abstract
Sperm contain microRNAs (miRNAs), which may have roles in epigenetic control. Regarding phylogenetic relationships among various swine breeds, Yorkshire and Landrace, are considered phenotypically and genetically very similar, but distinctly different from Duroc. The objective of the present study was to compare abundance of boar sperm miRNAs in these three breeds. Overall, 252 prioritized miRNAs were investigated using real-time PCR; relative expression of miRNAs in sperm was similar in Yorkshire and Landrace boars, but significantly different compared to Duroc. Seventeen miRNAs (hsa-miR-196a-5p, hsa-miR-514a-3p, hsa-miR-938, hsa-miR-372-3p, hsa-miR-558, hsa-miR-579-3p, hsa-miR-595, hsa-miR-648, hsa-miR-524-3p, hsa-miR-512-3p, hsa-miR-429, hsa-miR-639, hsa-miR-551a, hsa-miR-624-5p, hsa-miR-585-3p, hsa-miR-508-3p and hsa-miR-626) were down-regulated (P < 0.05; fold regulation ≤-2) in Yorkshire and Landrace sperm, compared to Duroc sperm. Furthermore, three miRNAs (hsa-miR-9-5p, hsa-miR-150-5p, and hsa-miR-99a-5p) were significantly up-regulated in Yorkshire and Landrace sperm compared to Duroc sperm, However, 240 miRNAs were not significantly different (within + 2 fold) between Yorkshire and Landrace sperm. We concluded that miRNAs in sperm were not significantly different between Yorkshire and Landrace boars, but there were significant differences between those two breeds and Duroc boars. Furthermore, integrated target genes for selected down-regulated miRNAs (identified via an in-silico method) appeared to participate in spermatogenesis and sperm functions.
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Affiliation(s)
- Vanmathy Kasimanickam
- Veterinary Clinical Sciences Department &Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA
| | - John Kastelic
- Department of Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4N2, Canada
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14
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Nixon E, Brooks JD, Routh PA, Chittenden JT, Baynes RE. Pharmacokinetics of14C-ortho-phenylphenol following intravenous administration in pigs. J Appl Toxicol 2016; 37:508-512. [DOI: 10.1002/jat.3380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 07/18/2016] [Accepted: 07/29/2016] [Indexed: 02/02/2023]
Affiliation(s)
- Emma Nixon
- Department of Population Health and Pathobiology, College of Veterinary Medicine; North Carolina State University; Raleigh NC USA
| | - James D. Brooks
- Department of Population Health and Pathobiology, College of Veterinary Medicine; North Carolina State University; Raleigh NC USA
| | - Patricia A. Routh
- Department of Population Health and Pathobiology, College of Veterinary Medicine; North Carolina State University; Raleigh NC USA
| | | | - Ronald E. Baynes
- Department of Population Health and Pathobiology, College of Veterinary Medicine; North Carolina State University; Raleigh NC USA
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15
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Lin Z, Vahl CI, Riviere JE. Human Food Safety Implications of Variation in Food Animal Drug Metabolism. Sci Rep 2016; 6:27907. [PMID: 27302389 PMCID: PMC4908408 DOI: 10.1038/srep27907] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 05/26/2016] [Indexed: 01/03/2023] Open
Abstract
Violative drug residues in animal-derived foods are a global food safety concern. The use of a fixed main metabolite to parent drug (M/D) ratio determined in healthy animals to establish drug tolerances and withdrawal times in diseased animals results in frequent residue violations in food-producing animals. We created a general physiologically based pharmacokinetic model for representative drugs (ceftiofur, enrofloxacin, flunixin, and sulfamethazine) in cattle and swine based on extensive published literature. Simulation results showed that the M/D ratio was not a fixed value, but a time-dependent range. Disease changed M/D ratios substantially and extended withdrawal times; these effects exhibited drug- and species-specificity. These results challenge the interpretation of violative residues based on the use of the M/D ratio to establish tolerances for metabolized drugs.
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Affiliation(s)
- Zhoumeng Lin
- Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
| | - Christopher I. Vahl
- Department of Statistics, College of Arts and Sciences, Kansas State University, Manhattan, KS 66506, USA
| | - Jim E. Riviere
- Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
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