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Attia KAM, El-Desouky EA, Abdelfatah AM, Abdelshafi NA. Simultaneous analysis of the of levamisole with triclabendazole in pharmaceuticals through developing TLC and HPLC-PDA chromatographic techniques and their greenness assessment using GAPI and AGREE methods. BMC Chem 2023; 17:163. [PMID: 37996961 PMCID: PMC10668390 DOI: 10.1186/s13065-023-01087-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023] Open
Abstract
Two simple and rapid chromatographic methods were developed and validated for the analysis of levamisole and triclabendazole simultaneously in pure and pharmaceutical products. The first method is thin-layer chromatography (TLC) with densitometry, and the second method is high-performance liquid chromatography with PDA detection (HPLC-PDA). A Hypersil BDS C18 column with dimensions of 4.6 × 150 mm and a particle size of 5 µm was used in the HPLC-PDA method. An isocratic condition was used to carry out the separation, and the mobile phase was made up of acetonitrile and a 0.03 M potassium dihydrogen phosphate buffer in double-distilled water. The ratio of the mobile phase preparation was 70:30 (v/v), and the flow rate was 1 mL/min. A wavelength of 215 nm was employed for analyte detection. Precoated silica gel 60 F254 aluminium plates were used for the TLC method's separation. Mobile phase was made of ethyl acetate, hexane, methanol, and ammonia (69:15:15:1) for the separation. The detection wavelength selected was 215 nm. According to the International Council for Harmonization (ICH) guidelines, the proposed methods were validated and it was found that the two chromatographic methods are accurate, precise, and linear for both compounds in the range of 3.75-37.5 and 6-60 mg/L for the HPLC method for levamisole and triclabendazole, respectively and in the range of 2-14 µg/spot for the TLC method. The developed methods greenness profile was assessed using AGREE and ComplexGAPI tools.
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Affiliation(s)
- Khalid A M Attia
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11751, Egypt
| | - Ebrahim A El-Desouky
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11751, Egypt
| | - Amr M Abdelfatah
- Department of Pharmaceutical Analytical Chemistry, School of Pharmacy, Badr University in Cairo, Badr City, Cairo, 11829, Egypt.
| | - Nahla A Abdelshafi
- Department of Pharmaceutical Analytical Chemistry, School of Pharmacy, Badr University in Cairo, Badr City, Cairo, 11829, Egypt.
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2
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Olivares-Ferretti P, Beltrán JF, Salazar LA, Fonseca-Salamanca F. Protein Modelling and Molecular Docking Analysis of Fasciola hepatica β-Tubulin's Interaction Sites, with Triclabendazole, Triclabendazole Sulphoxide and Triclabendazole Sulphone. Acta Parasitol 2023; 68:535-547. [PMID: 37330945 DOI: 10.1007/s11686-023-00692-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 05/29/2023] [Indexed: 06/20/2023]
Abstract
PURPOSE Fasciola hepatica is a globally distributed trematode that causes significant economic losses. Triclabendazole is the primary pharmacological treatment for this parasite. However, the increasing resistance to triclabendazole limits its efficacy. Previous pharmacodynamics studies suggested that triclabendazole acts by interacting mainly with the β monomer of tubulin. METHODS We used a high-quality method to model the six isotypes of F. hepatica β-tubulin in the absence of three-dimensional structures. Molecular dockings were conducted to evaluate the destabilization regions in the molecule against the ligands triclabendazole, triclabendazole sulphoxide and triclabendazole sulphone. RESULTS The nucleotide binding site demonstrates higher affinity than the binding sites of colchicine, albendazole, the T7 loop and pβVII (p < 0.05). We suggest that the binding of the ligands to the polymerization site of β-tubulin can lead a microtubule disruption. Furthermore, we found that triclabendazole sulphone exhibited significantly higher binding affinity than other ligands (p < 0.05) across all isotypes of β-tubulin. CONCLUSIONS Our investigation has yielded new insight on the mechanism of action of triclabendazole and its sulphometabolites on F. hepatica β-tubulin through computational tools. These findings have significant implications for ongoing scientific research ongoing towards the discovery of novel therapeutics to treat F. hepatica infections.
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Affiliation(s)
- Pamela Olivares-Ferretti
- Laboratory of Molecular Immunoparasitology, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Temuco, Chile
| | - Jorge F Beltrán
- Chemical Engineering Department, Faculty of Engineering and Science, Universidad de La Frontera, Temuco, Chile
| | - Luis A Salazar
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145, 4811230, Temuco, Chile
| | - Flery Fonseca-Salamanca
- Laboratory of Molecular Immunoparasitology, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Temuco, Chile.
- Preclinical Sciences Department, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile.
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3
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Chakroborty A, Pritchard DR, Bouillon ME, Cervi A, Kraehenbuehl R, Wild C, Fenn C, Holdsworth P, Capner C, Padalino G, Forde-Thomas JE, Payne J, Smith BG, Fisher M, Lahmann M, Baird MS, Hoffmann KF. Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica. Pharmaceutics 2023; 15:1869. [PMID: 37514055 PMCID: PMC10385850 DOI: 10.3390/pharmaceutics15071869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/30/2023] Open
Abstract
Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides.
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Affiliation(s)
- Anand Chakroborty
- The Department of Life Sciences (DLS), Aberystwyth University, Aberystwyth SY23 3DA, UK
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA
| | | | - Marc E Bouillon
- School of Natural Sciences, Bangor University, Bangor LL57 2UW, UK
| | - Anna Cervi
- Naturiol Bangor Ltd., MSParc, Gaerwen, Anglesey LL60 6AG, UK
| | | | - Charlotte Wild
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
| | - Caroline Fenn
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
| | - Peter Holdsworth
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
- PAH Consultancy Pty Ltd., 3/27 Gaunson Crescent, Wanniassa, Canberra 2903, Australia
| | - Colin Capner
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
| | - Gilda Padalino
- The Department of Life Sciences (DLS), Aberystwyth University, Aberystwyth SY23 3DA, UK
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK
| | | | - Joseph Payne
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
| | - Brendan G Smith
- Bimeda UK, Bryn Cefni Industrial Estate, Unit 2A, Llangefni LL77 7XA, UK
| | - Maggie Fisher
- Ridgeway Research Limited, Park Farm Buildings, Park Lane, St. Briavels, Gloucestershire GL15 6QX, UK
| | - Martina Lahmann
- School of Natural Sciences, Bangor University, Bangor LL57 2UW, UK
- KTH Royal Institute of Technology, Biomedical Engineering and Health Systems, Hälsovägen 11, 141 52 Huddinge, Sweden
| | - Mark S Baird
- Naturiol Bangor Ltd., MSParc, Gaerwen, Anglesey LL60 6AG, UK
| | - Karl F Hoffmann
- The Department of Life Sciences (DLS), Aberystwyth University, Aberystwyth SY23 3DA, UK
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Blanco-Paniagua E, Álvarez-Fernández L, Rodríguez-Alonso A, Millán-Garcia A, Álvarez AI, Merino G. Role of the Abcg2 Transporter in Secretion into Milk of the Anthelmintic Clorsulon: Interaction with Ivermectin. Antimicrob Agents Chemother 2023; 67:e0009523. [PMID: 37078871 PMCID: PMC10190675 DOI: 10.1128/aac.00095-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/30/2023] [Indexed: 04/21/2023] Open
Abstract
Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone ivermectin, it provides high broad-spectrum antiparasitic efficacy. The safety and efficacy of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the effect of ivermectin, a known ABCG2 inhibitor, on this process. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that clorsulon was transported in vitro by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg2-/- lactating female mice were used to carry out in vivo assays. The milk concentration and the milk-to-plasma ratio were higher in wild-type mice than in Abcg2-/- mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The interaction of ivermectin in this process was shown after the coadministration of clorsulon and ivermectin to wild-type and Abcg2-/- lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions mediated by ABCG2.
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Affiliation(s)
- Esther Blanco-Paniagua
- Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
| | - Laura Álvarez-Fernández
- Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
| | - Andrea Rodríguez-Alonso
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
| | - Alicia Millán-Garcia
- Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
| | - Ana I. Álvarez
- Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
| | - Gracia Merino
- Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain
- Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, León, Spain
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Secretion into Milk of the Main Metabolites of the Anthelmintic Albendazole Is Mediated by the ABCG2/BCRP Transporter. Antimicrob Agents Chemother 2022; 66:e0006222. [PMID: 35736132 PMCID: PMC9295555 DOI: 10.1128/aac.00062-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole 2-aminosulphone (ABZSO2-NH2). ABZSO and ABZSO2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO2 and ABZSO2-NH2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2-/- lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2-/- mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.
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Jala A, Ponneganti S, Vishnubhatla DS, Bhuvanam G, Mekala PR, Varghese B, Radhakrishnanand P, Adela R, Murty US, Borkar RM. Transporter-mediated drug-drug interactions: advancement in models, analytical tools, and regulatory perspective. Drug Metab Rev 2021; 53:285-320. [PMID: 33980079 DOI: 10.1080/03602532.2021.1928687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/05/2021] [Indexed: 02/08/2023]
Abstract
Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent in-silico approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from in-vitro to in-vivo, which may trigger the follow-up to clinical studies.
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Affiliation(s)
- Aishwarya Jala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Srikanth Ponneganti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Devi Swetha Vishnubhatla
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Gayathri Bhuvanam
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Prithvi Raju Mekala
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Bincy Varghese
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Pullapanthula Radhakrishnanand
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | - Ramu Adela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
| | | | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India
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7
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Yan L, Liu Y, Ma XF, Hou D, Zhang YH, Sun Y, Shi SS, Forouzanfar T, Lin HY, Fan J, Wu G. Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells. Front Pharmacol 2021; 12:670081. [PMID: 34305590 PMCID: PMC8297466 DOI: 10.3389/fphar.2021.670081] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022] Open
Abstract
Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME-N-terminal fragment cleavage and pyroptosis were reduced by caspase-3-specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.
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Affiliation(s)
- Liang Yan
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, China
| | - Yi Liu
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xue-feng Ma
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Dan Hou
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC/VUmc Location and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universitetit Amsterdam, Amsterdam Movement Science, Amsterdam, Netherlands
| | - Yu-hui Zhang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yong Sun
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, China
| | - Shan-shan Shi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Tim Forouzanfar
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC/VUmc Location and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universitetit Amsterdam, Amsterdam Movement Science, Amsterdam, Netherlands
| | - Hai-yan Lin
- Savaid Stomatology School, Hangzhou Medical College, Hangzhou, China
| | - Jun Fan
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, China
| | - Gang Wu
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC/VUmc Location and Academic Centre for Dentistry Amsterdam (ACTA), Vrije Universitetit Amsterdam, Amsterdam Movement Science, Amsterdam, Netherlands
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre of Dentistry Amsterdam (ACTA), Universiteit van Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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8
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Theoretical study of the geometric and electronic characterization of carbendazim-based drug (Nocodazole). Heliyon 2020; 6:e04055. [PMID: 32548318 PMCID: PMC7284080 DOI: 10.1016/j.heliyon.2020.e04055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/27/2020] [Accepted: 05/19/2020] [Indexed: 11/30/2022] Open
Abstract
Scarcity in studies defining the precise three-dimensional structure of approved drugs has led to an abandoning of their use for other therapeutic indications. In this manuscript, we solely focus on studying computationally the anticancer drug “Nocodazole” as a model compound for anthelmintic drugs –due to structural similarity– proven to exert anticancer activity such as Mebendazole and Albendazole. Computations on Nocodazole structures deposited in the Protein Data Bank (PDB) revealed possible existence of at least 6 conformers of Nocodazole. By combining the reported experimental UV-Vis data with our calculations, two conformers were assigned as the predominant structures of Nocodazole. In addition, td-DFT calculations revealed that the conformational flexibility of Nocodazole results in significant changes in atomic and molecular charge densities. The results have ramifications in identification of possible conformers of carbendazim-based drugs for repurposing in oncology through giving deep insights in understanding the spatial and electronic changes upon drug binding to anticancer targets.
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The Statistical Analysis of Pharmacokinetic Parameters in the Context of Bioequivalence Testing of Two Anthelmintic Formulas Based on Ivermectine and Triclabendazole in Sheep. ACTA MEDICA MARISIENSIS 2019. [DOI: 10.2478/amma-2019-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Conducting bioequivalence studies is an essential step during the market authorization process of generic pharmaceutical formulations, for both human or veterinary use. The aim of the present study was to evaluate the pharmacokinetics of triclabendazole sulphoxide, the main metabolite of triclabendazole, and ivermectin in order to evaluate the bioavailability and bioequivalence of a novel sheep anthelmintic formulation of oral suspension for sheep treatment containing triclabendazole 50 mg/mL and ivermectin 1 mg/mL compared to the reference product. In order to determine relative bioavailability of the test product with respect to the reference product the study was conducted on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. For the determination of triclabendazole sulphoxide and ivermectin sheep plasma concentrations, two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods were developed and validated. The measured plasma concentrations of triclabendazole sulphoxide and ivermectin were used for the pharmacokinetic analysis and the determination of bioequivalence between the test product with regards to the reference product. The noncompartmental analysis of the pharmacokinetic data for both triclabendazole sulphoxide and ivermectin showed similarities between first-order kinetics of the test and reference product. The relevant pharmacokinetic parameters (Cmax, AUClast, AUCtot) were determined and the bioequivalence between the test and reference product could be concluded.
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10
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Viviani P, Lifschitz AL, Luque SE, Lloberas MM, Maté ML, Cardozo PA, Lanusse CE, Virkel GL. Pharmacologic interaction between oxfendazole and triclabendazole: In vitro biotransformation and systemic exposure in sheep. Exp Parasitol 2019; 204:107718. [PMID: 31201779 DOI: 10.1016/j.exppara.2019.107718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 05/21/2019] [Accepted: 06/07/2019] [Indexed: 10/26/2022]
Abstract
The aim of the current work was to evaluate a potential pharmacokinetic interaction between the flukicide triclabendazole (TCBZ) and the broad-spectrum benzimidazole (BZD) anthelmintic oxfendazole (OFZ) in sheep. To this end, both an in vitro assay in microsomal fractions and an in vivo trial in lambs parasitized with Haemonchus contortus resistant to OFZ and its reduced derivative fenbendazole (FBZ) were carried out. Sheep microsomal fractions were incubated together with OFZ, FBZ, TCBZ, or a combination of either FBZ and TCBZ or OFZ and TCBZ. OFZ production was significantly diminished upon coincubation of FBZ and TCBZ, whereas neither FBZ nor OFZ affected the S-oxidation of TCBZ towards its sulfoxide and sulfone metabolites. For the in vivo trial, lambs were treated with OFZ (Vermox® oral drench at a single dose of 5 mg/kg PO), TCBZ (Fasinex® oral drench at a single dose of 12 mg/kg PO) or both compounds at a single dose of 5 (Vermox®) and 12 mg/kg (Fasinex®) PO. Blood samples were taken to quantify drug and metabolite concentrations, and pharmacokinetic parameters were calculated by means of non-compartmental analysis. Results showed that the pharmacokinetic parameters of active molecules and metabolites were not significantly altered upon coadministration. The sole exception was the increase in the mean residence time (MRT) of OFZ and FBZ sulfone upon coadministration, with no significant changes in the remaining pharmacokinetic parameters. This research is a further contribution to the study of metabolic drug-drug interactions that may affect anthelmintic efficacies in ruminants.
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Affiliation(s)
- P Viviani
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina
| | - A L Lifschitz
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina
| | - S E Luque
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina
| | - M M Lloberas
- Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Balcarce, (7620), Balcarce, Argentina
| | - M L Maté
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina
| | - P A Cardozo
- Instituto Nacional de Tecnología Agropecuaria (INTA), Estación Experimental Balcarce, (7620), Balcarce, Argentina
| | - C E Lanusse
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina
| | - G L Virkel
- Laboratorio de Farmacología, Centro de Investigación Veterinarias de Tandil (CIVETAN. CONICET-CIC-UNCPBA), Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA), Tandil, Argentina.
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11
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Martinez MN, Court MH, Fink-Gremmels J, Mealey KL. Population variability in animal health: Influence on dose-exposure-response relationships: Part I: Drug metabolism and transporter systems. J Vet Pharmacol Ther 2018; 41:E57-E67. [PMID: 29917248 DOI: 10.1111/jvp.12670] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/26/2018] [Accepted: 05/07/2018] [Indexed: 01/03/2023]
Abstract
There is an increasing effort to understand the many sources of population variability that can influence drug absorption, metabolism, disposition, and clearance in veterinary species. This growing interest reflects the recognition that this diversity can influence dose-exposure-response relationships and can affect the drug residues present in the edible tissues of food-producing animals. To appreciate the pharmacokinetic diversity that may exist across a population of potential drug product recipients, both endogenous and exogenous variables need to be considered. The American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session during the 2017 Biennial meeting to explore the sources of population variability recognized to impact veterinary medicine. The following review highlights the information shared during that session. In Part I of this workshop report, we consider sources of population variability associated with drug metabolism and membrane transport. Part II of this report highlights the use of modeling and simulation to support an appreciation of the variability in dose-exposure-response relationships.
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Affiliation(s)
- Marilyn N Martinez
- Center for Veterinary Medicine, US Food and Drug Administration, Rockville, Maryland
| | - Michael H Court
- Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington
| | - Johanna Fink-Gremmels
- Division of Pharmacology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands
| | - Katrina L Mealey
- Program in Individualized Medicine, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington
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Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: Compounds and therapeutic targets. PLoS Negl Trop Dis 2018; 12:e0006422. [PMID: 29677189 PMCID: PMC5931691 DOI: 10.1371/journal.pntd.0006422] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 05/02/2018] [Accepted: 03/31/2018] [Indexed: 02/06/2023] Open
Abstract
Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed, including the identification, development, and assessment of novel compound classes and drug targets. Here is presented a thorough overview of the range of compounds that have been tested against E. granulosus and E. multilocularis in recent years, including in vitro and in vivo data on their mode of action, dosage, administration regimen, therapeutic outcomes, and associated clinical symptoms. Drugs covered included albendazole, mebendazole, and other members of the benzimidazole family and their derivatives, including improved formulations and combined therapies with other biocidal agents. Chemically synthetized molecules previously known to be effective against other infectious and non-infectious conditions such as anti-virals, antibiotics, anti-parasites, anti-mycotics, and anti-neoplastics are addressed. In view of their increasing relevance, natural occurring compounds derived from plant and fungal extracts are also discussed. Special attention has been paid to the recent application of genomic science on drug discovery and clinical medicine, particularly through the identification of small inhibitor molecules tackling key metabolic enzymes or signalling pathways. Human cystic and alveolar echinococcosis (CE and AE), caused by the larval stages of the helminths Echinococcus granulosus and E. multilocularis, respectively, are progressive and chronic diseases affecting more than 1 million people worldwide. Both are considered orphan and neglected diseases by the World Health Organization. As a treatment approach, chemotherapy is limited to the use of benzimidazoles, drugs that stop parasite growth but do not kill the parasite. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed. Here, we present the state-of-the-art regarding the alternative compounds and new formulations of benzimidazoles assayed against these diseases until now. Some of these new and modified compounds, either alone or in combination, could represent a step forward in the treatment of CE and AE. Unfortunately, few compounds have reached clinical trials stage in humans and, when assayed, the design of these studies has not allowed evidence-based conclusions. Thus, there is still an urgent need for defining new compounds or improved formulations of those already assayed, and also for a careful design of clinical protocols that could lead to the draw of a broad international consensus on the use of a defined drug, or a combination of drugs, for the effective treatment of CE and AE.
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Viviani P, Lifschitz AL, Maté ML, García JP, Lanusse CE, Virkel GL. Assessment of the pharmacological interactions between the nematodicidal fenbendazole and the flukicidal triclabendazole: In vitro studies with bovine liver microsomes and slices. J Vet Pharmacol Ther 2018; 41:476-484. [DOI: 10.1111/jvp.12492] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 01/16/2018] [Indexed: 12/15/2022]
Affiliation(s)
- P. Viviani
- Facultad de Ciencias Veterinarias; Laboratorio de Farmacología; Centro de Investigación Veterinarias de Tandil (CIVETAN-CONICET-CICPBA); Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
| | - A. L. Lifschitz
- Facultad de Ciencias Veterinarias; Laboratorio de Farmacología; Centro de Investigación Veterinarias de Tandil (CIVETAN-CONICET-CICPBA); Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
| | - M. L. Maté
- Facultad de Ciencias Veterinarias; Laboratorio de Farmacología; Centro de Investigación Veterinarias de Tandil (CIVETAN-CONICET-CICPBA); Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
| | - J. P. García
- Facultad de Ciencias Veterinarias; Área Clínica de Grandes Animales; Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
| | - C. E. Lanusse
- Facultad de Ciencias Veterinarias; Laboratorio de Farmacología; Centro de Investigación Veterinarias de Tandil (CIVETAN-CONICET-CICPBA); Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
| | - G. L. Virkel
- Facultad de Ciencias Veterinarias; Laboratorio de Farmacología; Centro de Investigación Veterinarias de Tandil (CIVETAN-CONICET-CICPBA); Universidad Nacional del Centro de la Provincia de Buenos Aires (FCV-UNCPBA); Tandil Argentina
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Giri P, Gupta L, Naidu S, Joshi V, Patel N, Giri S, Srinivas NR. In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone. Drug Metab Lett 2018; 12:101-116. [PMID: 30117405 PMCID: PMC6416464 DOI: 10.2174/1872312812666180816164626] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 07/31/2018] [Accepted: 08/08/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND The use of polypharmacy in the present day clinical therapy has made the identification of clinical drug-drug interaction risk an important aspect of drug development process. Although many drugs can be metabolized to sulfoxide and/or sulfone metabolites, seldom is known on the CYP inhibition potential and/or the metabolic fate for such metabolites. OBJECTIVE The key objectives were: a) to evaluate the in vitro CYP inhibition potential of selected parent drugs with sulfoxide/sulfone metabolites; b) to assess the in vitro metabolic fate of the same panel of parent drugs and metabolites. METHODS In vitro drug-drug interaction potential of test compounds was investigated in two stages; 1) assessment of CYP450 inhibition potential of test compounds using human liver microsomes (HLM); and 2) assessment of test compounds as substrate of Phase I enzymes; including CYP450, FMO, AO and MAO using HLM, recombinant human CYP enzymes (rhCYP), Human Liver Cytosol (HLC) and Human Liver Mitochondrial (HLMit). All samples were analysed by LC-MS-MS method. RESULTS CYP1A2 was inhibited by methiocarb, triclabendazole, triclabendazole sulfoxide, and ziprasidone sulfone with IC50 of 0.71 µM, 1.07 µM, 4.19 µM, and 17.14 µM, respectively. CYP2C8 was inhibited by montelukast, montelukast sulfoxide, montelukast sulfone, tribendazole, triclabendazole sulfoxide, and triclabendazole sulfone with IC50 of 0.08 µM, 0.05 µM, 0.02 µM, 3.31 µM, 8.95 µM, and 1.05 µM, respectively. CYP2C9 was inhibited by triclabendazole, triclabendazole sulfoxide, triclabendazole sulfone, montelukast, montelukast sulfoxide and montelukast sulfone with IC50 of 1.17 µM, 1.95 µM, 0.69 µM, 1.34 µM, 3.61 µM and 2.15 µM, respectively. CYP2C19 was inhibited by triclabendazole and triclabendazole sulfoxide with IC50 of 0.25 and 0.22, respectively. CYP3A4 was inhibited by montelukast sulfoxide and triclabendazole with IC50 of 9.33 and 15.11, respectively. Amongst the studied sulfoxide/sulfone substrates, the propensity of involvement of CY2C9 and CYP3A4 enzyme was high (approximately 56% of total) in the metabolic fate experiments. CONCLUSION Based on the findings, a proper risk assessment strategy needs to be factored (i.e., perpetrator and/or victim drug) to overcome any imminent risk of potential clinical drug-drug interaction when sulfoxide/sulfone metabolite(s) generating drugs are coadministered in therapy.
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Affiliation(s)
| | | | | | | | | | | | - Nuggehally R. Srinivas
- Address correspondence to this author at the Cadila Health Care Ltd. (Zydus Research Centre) Survey No. 396/403, NH-8A, Tal-Sanand, Ahmedabad, Moraiya, Gujarat, Pin-382213, India; Tel: +91-2717-665555; Fax: +91-2717-665355; E-mail:
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Ferretti R, Carradori S, Guglielmi P, Pierini M, Casulli A, Cirilli R. Enantiomers of triclabendazole sulfoxide: Analytical and semipreparative HPLC separation, absolute configuration assignment, and transformation into sodium salt. J Pharm Biomed Anal 2017; 140:38-44. [PMID: 28340473 DOI: 10.1016/j.jpba.2017.03.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 03/10/2017] [Accepted: 03/11/2017] [Indexed: 11/17/2022]
Abstract
Direct HPLC separation of the enantiomers of triclabendazole sulfoxide (TCBZ-SO), which is the main metabolite of the anthelmintic drug triclabendazole, was carried out using the polysaccharide-based Chiralpak AS-H and Chiralpak IF-3 chiral stationary phases (CSPs). The chromatographic behaviour of both CSPs was evaluated and compared using normal-phase and reversed-phase eluents at different column temperatures. The eluent mixture of n-hexane-2-propanol-trifluoroacetic acid 70:30:0.1 (v/v/v) and a column temperature of 40°C were identified as the best operational conditions to carry out semipreparative enantioseparations on a 1-cm I.D. AS-H column. Under these conditions, 12.5mg of racemic sample were resolved in a single chromatographic run within 15min. Comparison of calculated and experimental chiroptical properties provided the absolute configuration assignment at the sulfur atom. The salification of the isolated enantiomers of TCBZ-SO by reaction with sodium hydroxide solution produced water-soluble Na salts which are potentially useful in the development of new anthelmintic enantiomerically pure formulations.
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Affiliation(s)
- Rosella Ferretti
- Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy
| | - Simone Carradori
- Dipartimento di Farmacia, Università "G. D'Annunzio" di Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Paolo Guglielmi
- Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, 00185 Rome, Italy
| | - Marco Pierini
- Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, 00185 Rome, Italy
| | - Adriano Casulli
- Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy; World Health Organization Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy
| | - Roberto Cirilli
- Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
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Peña-Solórzano D, Stark SA, König B, Sierra CA, Ochoa-Puentes C. ABCG2/BCRP: Specific and Nonspecific Modulators. Med Res Rev 2016; 37:987-1050. [PMID: 28005280 DOI: 10.1002/med.21428] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/17/2016] [Accepted: 11/03/2016] [Indexed: 12/13/2022]
Abstract
Multidrug resistance (MDR) in cancer cells is the development of resistance to a variety of structurally and functionally nonrelated anticancer drugs. This phenomenon has become a major obstacle to cancer chemotherapy seriously affecting the clinical outcome. MDR is associated with increased drug efflux from cells mediated by an energy-dependent mechanism involving the ATP-binding cassette (ABC) transporters, mainly P-glycoprotein (ABCB1), the MDR-associated protein-1 (ABCC1), and the breast cancer resistance protein (ABCG2). The first two transporters have been widely studied already and reviews summarized the results. The ABCG2 protein has been a subject of intense study since its discovery as its overexpression has been detected in resistant cell lines in numerous types of human cancers. To date, a long list of modulators of ABCG2 exists and continues to increase. However, little is known about the clinical consequences of ABCG2 modulation. This makes the design of novel, potent, and nontoxic inhibitors of this efflux protein a major challenge to reverse MDR and thereby increase the success of chemotherapy. The aim of the present review is to describe and highlight specific and nonspecific modulators of ABCG2 reported to date based on the selectivity of the compounds, as many of them are effective against one or more ABC transport proteins.
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Affiliation(s)
- Diana Peña-Solórzano
- Grupo de Investigación en Macromoléculas, Departamento de Química, Universidad Nacional de Colombia-Sede Bogotá, 5997, Bogotá, Colombia
| | | | - Burkhard König
- Institute of Organic Chemistry, University of Regensburg, 93040 Regensburg, Germany
| | - Cesar Augusto Sierra
- Grupo de Investigación en Macromoléculas, Departamento de Química, Universidad Nacional de Colombia-Sede Bogotá, 5997, Bogotá, Colombia
| | - Cristian Ochoa-Puentes
- Grupo de Investigación en Macromoléculas, Departamento de Química, Universidad Nacional de Colombia-Sede Bogotá, 5997, Bogotá, Colombia
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Halwachs S, Kneuer C, Gohlsch K, Müller M, Ritz V, Honscha W. The ABCG2 efflux transporter from rabbit placenta: Cloning and functional characterization. Placenta 2015; 38:8-15. [PMID: 26907376 DOI: 10.1016/j.placenta.2015.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 11/12/2015] [Accepted: 12/10/2015] [Indexed: 01/01/2023]
Abstract
In human placenta, the ATP-binding cassette efflux transporter ABCG2 is highly expressed in syncytiotrophoblast cells and mediates cellular excretion of various drugs and toxins. Hence, physiological ABCG2 activity substantially contributes to the fetoprotective placenta barrier function during gestation. Developmental toxicity studies are often performed in rabbit. However, despite its toxicological relevance, there is no data so far on functional ABCG2 expression in this species. Therefore, we cloned ABCG2 from placenta tissues of chinchilla rabbit. Sequencing showed 84-86% amino acid sequence identity to the orthologues from man, rat and mouse. We transduced the rabbit ABCG2 clone (rbABCG2) in MDCKII cells and stable rbABCG2 gene and protein expression was shown by RT-PCR and Western blot analysis. The rbABCG2 efflux activity was demonstrated with the Hoechst H33342 assay using the specific ABCG2 inhibitor Ko143. We further tested the effect of established human ABCG2 (hABCG2) drug substrates including the antibiotic danofloxacin or the histamine H2-receptor antagonist cimetidine on H33342 accumulation in MDCKII-rbABCG2 or -hABCG2 cells. Human therapeutic plasma concentrations of all tested drugs caused a comparable competitive inhibition of H33342 excretion in both ABCG2 clones. Altogether, we first showed functional expression of the ABCG2 efflux transporter in rabbit placenta. Moreover, our data suggest a similar drug substrate spectrum of the rabbit and the human ABCG2 efflux transporter.
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Affiliation(s)
- Sandra Halwachs
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, D-04103 Leipzig, Germany.
| | - Carsten Kneuer
- Federal Institute for Risk Assessment (BfR), Pesticide Safety, Max-Dohrn-Straße 8-10, D-10589 Berlin, Germany.
| | - Katrin Gohlsch
- Federal Institute for Risk Assessment (BfR), Pesticide Safety, Max-Dohrn-Straße 8-10, D-10589 Berlin, Germany.
| | - Marian Müller
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, D-04103 Leipzig, Germany.
| | - Vera Ritz
- Federal Institute for Risk Assessment (BfR), Pesticide Safety, Max-Dohrn-Straße 8-10, D-10589 Berlin, Germany.
| | - Walther Honscha
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, D-04103 Leipzig, Germany.
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Wen JH, Wei XH, Sheng XY, Zhou DQ, Peng HW, Lu YN, Zhou J. Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro. CHINESE MEDICAL SCIENCES JOURNAL = CHUNG-KUO I HSUEH K'O HSUEH TSA CHIH 2015; 30:218-25. [PMID: 26960302 DOI: 10.1016/s1001-9294(16)30004-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro. METHODS Firstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells. RESULTS As a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. CONCLUSION Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.
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Affiliation(s)
- Jin-hua Wen
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiao-hua Wei
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiang-yuan Sheng
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - De-qing Zhou
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Hong-wei Peng
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Yan-ni Lu
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Jian Zhou
- Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
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Prediction of Drug Transfer into Milk Considering Breast Cancer Resistance Protein (BCRP)-Mediated Transport. Pharm Res 2015; 32:2527-37. [PMID: 25690342 DOI: 10.1007/s11095-015-1641-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 01/27/2015] [Indexed: 01/13/2023]
Abstract
PURPOSE Drug transfer into milk is of concern due to the unnecessary exposure of infants to drugs. Proposed prediction methods for such transfer assume only passive drug diffusion across the mammary epithelium. This study reorganized data from the literature to assess the contribution of carrier-mediated transport to drug transfer into milk, and to improve the predictability thereof. METHODS Milk-to-plasma drug concentration ratios (M/Ps) in humans were exhaustively collected from the literature and converted into observed unbound concentration ratios (M/Punbound,obs). The ratios were also predicted based on passive diffusion across the mammary epithelium (M/Punbound,pred). An in vitro transport assay was performed for selected drugs in breast cancer resistance protein (BCRP)-expressing cell monolayers. RESULTS M/Punbound,obs and M/Punbound,pred values were compared for 166 drugs. M/Punbound,obs values were 1.5 times or more higher than M/Punbound,pred values for as many as 13 out of 16 known BCRP substrates, reconfirming BCRP as the predominant transporter contributing to secretory transfer of drugs into milk. Predictability of M/P values for selected BCRP substrates and non-substrates was improved by considering in vitro-evaluated BCRP-mediated transport relative to passive diffusion alone. CONCLUSIONS The current analysis improved the predictability of drug transfer into milk, particularly for BCRP substrates, based on an exhaustive data overhaul followed by focused in vitro transport experimentation.
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Iezzi S, Lifschitz A, Sallovitz J, Nejamkin P, Lloberas M, Manazza J, Lanusse C, Imperiale F. Closantel plasma and milk disposition in dairy goats: assessment of drug residues in cheese and ricotta. J Vet Pharmacol Ther 2014; 37:589-94. [DOI: 10.1111/jvp.12135] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 05/02/2014] [Indexed: 12/23/2022]
Affiliation(s)
- S. Iezzi
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
| | - A. Lifschitz
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
| | - J. Sallovitz
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
| | - P. Nejamkin
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
| | - M. Lloberas
- Instituto Nacional de Tecnología Agropecuaria (INTA); Estación Experimental Balcarce; Balcarce Argentina
| | - J. Manazza
- Instituto Nacional de Tecnología Agropecuaria (INTA); Estación Experimental Balcarce; Balcarce Argentina
| | - C. Lanusse
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
| | - F. Imperiale
- Laboratorio de Farmacología; Centro de Investigación Veterinaria de Tandil (CIVETAN); CONICET/CICPBA; Facultad de Ciencias Veterinarias; UNCPBA; Tandil Argentina
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Stuurman FE, Nuijen B, Beijnen JH, Schellens JHM. Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement. Clin Pharmacokinet 2013; 52:399-414. [PMID: 23420518 DOI: 10.1007/s40262-013-0040-2] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug's stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are unacceptable variation in the bioavailability and high investment costs. Furthermore, novel oral anticancer drugs are frequently associated with toxic effects including unacceptable gastrointestinal adverse effects. Therefore, compliance is often suboptimal, which may negatively influence treatment outcome.
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Affiliation(s)
- Frederik E Stuurman
- Division of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Barrera B, González-Lobato L, Otero JA, Real R, Prieto JG, Álvarez AI, Merino G. Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter. Vet J 2013; 198:429-36. [DOI: 10.1016/j.tvjl.2013.07.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 07/18/2013] [Accepted: 07/28/2013] [Indexed: 01/16/2023]
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Bircsak KM, Richardson JR, Aleksunes LM. Inhibition of human MDR1 and BCRP transporter ATPase activity by organochlorine and pyrethroid insecticides. J Biochem Mol Toxicol 2013; 27:157-64. [PMID: 23169446 PMCID: PMC4001733 DOI: 10.1002/jbt.21458] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 10/04/2012] [Accepted: 10/13/2012] [Indexed: 01/30/2023]
Abstract
Despite the growing evidence suggesting that pesticides contribute to chronic diseases, there is a limited understanding of how these chemicals are removed from cells and whether pesticides can alter the disposition of drugs. The present study examined the effects of two classes of insecticides (organochlorine and pyrethroid) on the ATPase activity of the human multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) efflux transporters. Using plasma membranes from cells overexpressing MDR1 and BCRP, it was demonstrated that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) (o,p'-DDT and p,p'-DDT isomers) as well as its metabolite (p,p'-dichlorodiphenyldichloroethane), inhibit both MDR1 and BCRP ATPase activity. In addition, p,p'-dichlorodiphenyldichloroethylene, and two pyrethroid pesticides inhibited BCRP ATPase activity between 4 and 7 μM. Additional research is necessary to further characterize the functional inhibition of MDR1 and BCRP activity and determine whether pesticides alter the transporter-mediated disposition of other chemicals.
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Affiliation(s)
- Kristin M Bircsak
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
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