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Corum O, Uney K, Coskun D, Durna Corum D, Cetin G, Elmas M. Plasma and Milk Pharmacokinetics and Estimated Milk Withdrawal Time of Tolfenamic Acid in Lactating Sheep. Vet Med Sci 2024; 10:e70047. [PMID: 39321188 PMCID: PMC11423908 DOI: 10.1002/vms3.70047] [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: 05/29/2024] [Revised: 08/23/2024] [Accepted: 09/06/2024] [Indexed: 09/27/2024] Open
Abstract
OBJECTIVE This study aimed to investigate the plasma and milk pharmacokinetics, as well as the withdrawal time (WT) from milk of tolfenamic acid (2 and 4 mg/kg) following intravenous (IV) administration to eight healthy lactating Akkaraman sheep. METHODS The trial was conducted in two periods in accordance with a crossover pharmacokinetic design. The concentrations of tolfenamic acid in the plasma and milk were determined using high-pressure liquid chromatography and evaluated using non-compartmental analysis. The WT of tolfenamic acid in milk was calculated using the WT 1.4 software. RESULTS Compared to the 2 mg/kg dose, plasma volume of distribution at steady state (from 0.43 to 0.50 L/kg), terminal elimination half-life (from 2.41 to 4.14 h) and dose-normalized area under the plasma concentration-time curve (AUC0-∞, from 9.46 to 30.11 h µg/mL) increased, whereas total body clearance (from 0.21 to 0.13 L/h/kg) decreased at the 4 mg/kg dose. The peak milk concentration (Cmax) and AUC0-∞ values in milk were 0.26 µg/mL and 0.28 h µg/mL, respectively, for 2 mg/kg, and 0.43 µg/mL and 0.55 h µg/mL, respectively, for 4 mg/kg. Although the dose-normalized Cmax of milk decreased depending on the dose, no difference was observed in dose-normalized AUC0-∞. The AUC0-∞ milk/AUC0-∞ plasma ratio was 0.03 for 2 mg/kg and 0.02 for 4 mg/kg. The WT values calculated for milk at dosages of 2 and 4 mg/kg were 3 and 4 h, respectively. CONCLUSIONS A decrease in plasma elimination and an increase in plasma concentration of tolfenamic acid were observed depending on the dose. Tolfenamic acid lowly passed into sheep's milk at 2 and 4 mg/kg doses. This study may provide valuable information for clinicians' decision-making processes.
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Affiliation(s)
- Orhan Corum
- Department of Pharmacology and ToxicologyFaculty of Veterinary MedicineUniversity of Hatay Mustafa KemalAntakyaHatayTürkiye
| | - Kamil Uney
- Department of Pharmacology and ToxicologyFaculty of Veterinary MedicineUniversity of SelcukKonyaTürkiye
| | - Devran Coskun
- Department of Pharmacology and ToxicologyFaculty of Veterinary MedicineUniversity of SiirtSiirtTürkiye
| | - Duygu Durna Corum
- Department of Pharmacology and ToxicologyFaculty of Veterinary MedicineUniversity of Hatay Mustafa KemalAntakyaHatayTürkiye
| | - Gul Cetin
- Department of PharmacologyFaculty of PharmacyUniversity of Erzincan Binali YıldırımErzincanTürkiye
| | - Muammer Elmas
- Department of Pharmacology and ToxicologyFaculty of Veterinary MedicineUniversity of SelcukKonyaTürkiye
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Kazi SH, Sheraz MA, Anwar Z, Musharraf SG, Ahmed S, Bano R, Mirza T, Heo K, Na JH. Photolysis of tolfenamic acid in aqueous and organic solvents: a kinetic study. RSC Adv 2024; 14:21383-21397. [PMID: 38979457 PMCID: PMC11228578 DOI: 10.1039/d4ra01369g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 06/27/2024] [Indexed: 07/10/2024] Open
Abstract
Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug that was studied for its photodegradation in aqueous (pH 2.0-12.0) and organic solvents (acetonitrile, methanol, ethanol, 1-propanol, 1-butanol). TA follows first-order kinetics for its photodegradation, and the apparent first-order rate constants (k obs) are in the range of 0.65 (pH 12.0) to 6.94 × 10-2 (pH 3.0) min-1 in aqueous solution and 3.28 (1-butanol) to 7.69 × 10-4 (acetonitrile) min-1 in organic solvents. The rate-pH profile for TA photodegradation is an inverted V (∧) or V-top shape, indicating that the cationic form is more susceptible to acid hydrolysis than the anionic form of TA, which is less susceptible to alkaline hydrolysis. The fluorescence behavior of TA also exhibits a V-top-shaped curve, indicating maximum fluorescence intensity at pH 3.0. TA is highly stable at a pH range of 5.0-7.0, making it suitable for formulation development. In organic solvents, the photodegradation rate of TA increases with the solvent's dielectric constant and solvent acceptor number, indicating solute-solvent interactions. The values of k obs decreased with increased viscosity of the solvents due to diffusion-controlled processes. The correlation between k obs versus ionization potential and solvent density has also been established. A total of 17 photoproducts have been identified through LC-MS, of which nine have been reported for the first time. It has been confirmed through electron spin resonance (ESR) spectrometry that the excited singlet state of TA is converted into an excited triplet state through intersystem crossing, which results in an increased rate of photodegradation in acetonitrile.
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Affiliation(s)
- Sadia Hafeez Kazi
- Department of Pharmaceutics, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University Karachi-75340 Pakistan
| | - Muhammad Ali Sheraz
- Department of Pharmaceutics, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University Karachi-75340 Pakistan
| | - Zubair Anwar
- Department of Pharmaceutical Chemistry, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University Karachi-75340 Pakistan
| | - Syed Ghulam Musharraf
- Third World Center for Science and Technology, H.E.J. Research Institute of Chemistry, University of Karachi Karachi-75270 Pakistan
| | - Sofia Ahmed
- Department of Pharmaceutics, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University Karachi-75340 Pakistan
| | - Raheela Bano
- Dow College of Pharmacy, Dow University of Health Sciences (Ojha Campus) Karachi Pakistan
| | - Tania Mirza
- Department of Pharmaceutical Chemistry, Baqai Institute of Pharmaceutical Sciences, Baqai Medical University Karachi-75340 Pakistan
| | - Kyuyoung Heo
- Reliability Assessment Center, Korea Research Institute of Chemical Technology Daejeon 34114 Republic of Korea
| | - Jun-Hee Na
- Department of Convergence System Engineering, Chungnam National University Daejeon 34134 Republic of Korea
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Corum O, Durna Corum D, Marin P, Acar OF, Aksoy M, Uney K. Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss). Vet Med Sci 2024; 10:e1533. [PMID: 38952278 PMCID: PMC11217592 DOI: 10.1002/vms3.1533] [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: 05/13/2024] [Revised: 06/05/2024] [Accepted: 06/14/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. OBJECTIVES The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. METHODS The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. RESULTS The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. CONCLUSIONS While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.
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Affiliation(s)
- Orhan Corum
- Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of Hatay Mustafa KemalHatayTurkiye
| | - Duygu Durna Corum
- Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of Hatay Mustafa KemalHatayTurkiye
| | - Pedro Marin
- Department of Pharmacology, Faculty of Veterinary MedicineUniversity of MurciaMurciaSpain
| | - Omer Faruk Acar
- Faculty of Veterinary MedicineUniversity of KastamonuKastamonuTurkiye
| | - Mert Aksoy
- Faculty of Veterinary MedicineUniversity of KastamonuKastamonuTurkiye
| | - Kamil Uney
- Department of Pharmacology and Toxicology, Faculty of Veterinary MedicineUniversity of SelcukKonyaTurkiye
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Loeffler DA. Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches. Front Aging Neurosci 2024; 16:1368200. [PMID: 38872626 PMCID: PMC11170721 DOI: 10.3389/fnagi.2024.1368200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/01/2024] [Indexed: 06/15/2024] Open
Abstract
Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.
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Affiliation(s)
- David A. Loeffler
- Department of Neurology, Beaumont Research Institute, Corewell Health, Royal Oak, MI, United States
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Álvarez-Fernández L, Blanco-Paniagua E, Merino G. ABCG2 Transports the Flukicide Nitroxynil and Affects Its Biodistribution and Secretion into Milk. Pharmaceutics 2024; 16:558. [PMID: 38675219 PMCID: PMC11054271 DOI: 10.3390/pharmaceutics16040558] [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: 03/13/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
The ABCG2 transporter plays a key role in pharmacological and toxicological processes, affecting bioavailability, tissue accumulation and milk secretion of its substrates. This protein is expressed in several biological barriers acting as a protective mechanism against xenobiotic exposure by pumping out a broad range of compounds. However, its induced expression during lactation in alveolar cells of mammary gland represents a relevant route for active transport of unwanted chemicals into milk. This work aimed to characterize the involvement of ABCG2 in systemic exposure and milk secretion of the flukicide nitroxynil. Using MDCK-II cells overexpressing the transporter, we showed that nitroxynil is an in vitro substrate of different species variants of ABCG2. Moreover, using wild-type and Abcg2-/- mice, we showed that murine Abcg2 clearly affects plasma levels of nitroxynil. We also reported differences in nitroxynil accumulation in several tissues, with almost 2-fold higher concentration in kidney, small intestine and testis of Abcg2-/- mice. Finally, we proved that nitroxynil secretion into milk was also affected by Abcg2, with a 1.9-fold higher milk concentration in wild-type compared with Abcg2-/- mice. We conclude that ABCG2 significantly impacts nitroxynil biodistribution by regulating its passage across biological barriers.
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Affiliation(s)
| | | | - Gracia Merino
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), University of León, Campus de Vegazana s/n, 24071 León, Spain; (L.Á.-F.); (E.B.-P.)
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Álvarez-Fernández L, Blanco-Paniagua E, Millán-García A, Velasco-Díez M, Álvarez AI, Merino G. The ABCG2 protein in vitro transports the xenobiotic thiabendazole and increases the appearance of its residues in milk. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 107:104421. [PMID: 38493880 DOI: 10.1016/j.etap.2024.104421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/13/2024] [Accepted: 03/15/2024] [Indexed: 03/19/2024]
Abstract
Thiabendazole (TBZ) is a broad-spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5-hydroxythiabendazole (5OH-TBZ), the main TBZ metabolite. Using MDCK-II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH-TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH-TBZ secretion into milk was affected by Abcg2, with a more than 2-fold higher milk concentration and milk to plasma ratio in wild-type mice compared to their Abcg2-/- counterpart.
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Affiliation(s)
- Laura Álvarez-Fernández
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain
| | - Esther Blanco-Paniagua
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain
| | - Alicia Millán-García
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain
| | - Miriam Velasco-Díez
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain
| | - Ana I Álvarez
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain
| | - Gracia Merino
- Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Animal Health Institute (INDEGSAL), 24071, Universidad de León, Campus de Vegazana, León, Spain.
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Kazi SH, Sheraz MA, Musharraf SG, Ahmed S, Bano R, Haq FU, Anwar Z, Ali R. Analysis of Tolfenamic Acid using a Simple, Rapid, and Stability-indicating Validated HPLC Method. Antiinflamm Antiallergy Agents Med Chem 2024; 23:52-70. [PMID: 37291774 DOI: 10.2174/1871523022666230608094152] [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: 03/03/2023] [Revised: 05/13/2023] [Accepted: 05/25/2023] [Indexed: 06/10/2023]
Abstract
BACKGROUND Tolfenamic acid (TA) belongs to the fenamates class of nonsteroidal anti-inflammatory drugs. Insufficient information is available regarding the availability of a reliable and validated stability-indicating method for the assay of TA. OBJECTIVE A relatively simple, rapid, accurate, precise, economical, robust, and stabilityindicating RP-HPLC method has been developed to determine TA in pure and tablet dosage forms. METHODS The method was validated according to the ICH guideline, and parameters like linearity, range, selectivity, accuracy, precision, robustness, specificity, and solution stability were determined. TLC and FTIR spectrometry were used to ascertain the purity of TA. The specificity was determined with known impurities and after performing forced degradation, while the robustness was established by Plackett-Burman's experimental design. The mobile phase used for the analysis was acetonitrile and water (90:10, v/v) at pH 2.5. The detection of the active drug was made at 280 nm using a C18 column (tR = 4.3 min.). The method's applicability was also checked for the yellow polymorphic form of TA. RESULTS The results indicated that the method is highly accurate (99.39-100.80%), precise (<1.5% RSD), robust (<2% RSD), and statistically comparable to the British Pharmacopoeia method with better sensitivity and specificity. CONCLUSION It was observed that the stress degradation studies do not affect the method's accuracy and specificity. Hence the proposed method can be used to assay TA and its tablet dosage form.
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Affiliation(s)
- Sadia Hafeez Kazi
- Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 75340, Karachi, Pakistan
| | - Muhammad Ali Sheraz
- Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 75340, Karachi, Pakistan
| | - Syed Ghulam Musharraf
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270, Karachi, Pakistan
| | - Sofia Ahmed
- Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 75340, Karachi, Pakistan
| | - Raheela Bano
- Dow College of Pharmacy, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Faraz Ul Haq
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270, Karachi, Pakistan
| | - Zubair Anwar
- Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 75340, Karachi, Pakistan
| | - Raahim Ali
- Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 75340, Karachi, Pakistan
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8
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Ben Halima N, Álvarez-Fernández L, Blanco-Paniagua E, Abid-Essefi S, Guedri Y, Merino G. In vitro interaction of the pesticides flupyradifurone, bupirimate and its metabolite ethirimol with the ATP-binding cassette transporter G2 (ABCG2). Toxicol Lett 2023; 380:23-30. [PMID: 37011773 DOI: 10.1016/j.toxlet.2023.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/06/2023] [Accepted: 03/31/2023] [Indexed: 04/03/2023]
Abstract
ABCG2 is an ATP-binding cassette efflux transporter that is expressed in absorptive and excretory organs such as liver, intestine, kidney, brain and testis where it plays a crucial physiological and toxicological role in protecting cells against xenobiotics, affecting pharmacokinetics of its substrates. In addition, the induction of ABCG2 expression in mammary gland during lactation is related to active secretion of many toxicants into milk. In this study, the in vitro interactions between ABCG2 and three pesticides flupyradifurone, bupirimate and its metabolite ethirimol were investigated to check whether these compounds are substrates and/or inhibitors of this transporter. Using in vitro transepithelial assays with cells transduced with murine, ovine and human ABCG2, we showed that ethirimol and flupyradifurone were transported efficiently by murine Abcg2 and ovine ABCG2 but not by human ABCG2. Bupirimate was not found to be an in vitro substrate of ABCG2 transporter. Accumulation assays using mitoxantrone in transduced MDCK-II cells suggest that none of the tested pesticides were efficient ABCG2 inhibitors, at least in our experimental conditions. Our studies disclose that ethirimol and flupyradifurone are in vitro substrates of murine and ovine ABCG2, opening the possibility of a potential relevance of ABCG2 in the toxicokinetics of these pesticides.
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Affiliation(s)
- Nada Ben Halima
- Laboratory for Research on Biologically Compatible Compounds, Faculty of Dental Medicine, University of Monastir, Avicenne Street, 5019, Monastir, Tunisia; Faculty of Pharmacy, University of Monastir, Tunisia
| | - Laura Álvarez-Fernández
- Department of Biomedical Sciences-Physiology, Veterinary Faculty, Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana, 24071 Leon, Spain
| | - Esther Blanco-Paniagua
- Department of Biomedical Sciences-Physiology, Veterinary Faculty, Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana, 24071 Leon, Spain
| | - Salwa Abid-Essefi
- Laboratory for Research on Biologically Compatible Compounds, Faculty of Dental Medicine, University of Monastir, Avicenne Street, 5019, Monastir, Tunisia
| | - Yosra Guedri
- Department of Nephrology, Dialysis, and Renal Transplantation, Sahloul Universitary Hospital, Sousse, Tunisia
| | - Gracia Merino
- Department of Biomedical Sciences-Physiology, Veterinary Faculty, Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana, 24071 Leon, Spain.
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Liu J, Wang F, Wang X, Fan S, Li Y, Xu M, Hu H, Liu K, Zheng B, Wang L, Zhang H, Li J, Li W, Zhang W, Hu Z, Cao R, Zhuang X, Wang M, Zhong W. Antiviral effects and tissue exposure of tetrandrine against SARS-CoV-2 infection and COVID-19. MedComm (Beijing) 2023; 4:e206. [PMID: 36699286 PMCID: PMC9851407 DOI: 10.1002/mco2.206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 01/21/2023] Open
Abstract
Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.
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Affiliation(s)
- Jia Liu
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Furun Wang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Xi Wang
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Shiyong Fan
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Yufeng Li
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Mingyue Xu
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Hengrui Hu
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Ke Liu
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Bohong Zheng
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Lingchao Wang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Huanyu Zhang
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Jiang Li
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Wei Li
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Wenpeng Zhang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Zhihong Hu
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
| | - Ruiyuan Cao
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Xiaomei Zhuang
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
| | - Manli Wang
- State Key Laboratory of VirologyWuhan Institute of VirologyCenter for Biosafety Mega‐ScienceChinese Academy of SciencesWuhanChina
- Hubei Jiangxia LaboratoryWuhanChina
| | - Wu Zhong
- National Engineering Research Center for the Emergency DrugBeijing Institute of Pharmacology and ToxicologyBeijingChina
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Constantinescu T, Mihis AG. Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones. Int J Mol Sci 2022; 23:11595. [PMID: 36232899 PMCID: PMC9570335 DOI: 10.3390/ijms231911595] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
ATP-binding cassette subfamily G and tubulin pharmacological mechanisms decrease the effectiveness of anticancer drugs by modulating drug absorption and by creating tubulin assembly through polymerization. A series of natural and synthetic chalcones have been reported to have very good anticancer activity, with a half-maximal inhibitory concentration lower than 1 µM. By modulation, it is observed in case of the first mechanism that methoxy substituents on the aromatic cycle of acetophenone residue and substitution of phenyl nucleus by a heterocycle and by methoxy or hydroxyl groups have a positive impact. To inhibit tubulin, compounds bind to colchicine binding site. Presence of methoxy groups, amino groups or heterocyclic substituents increase activity.
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Affiliation(s)
- Teodora Constantinescu
- Department of Chemistry, Faculty of Pharmacy, Iuliu Hatieganu University, 400012 Cluj-Napoca, Romania
| | - Alin Grig Mihis
- Advanced Materials and Applied Technologies Laboratory, Institute of Research-Development-Innovation in Applied Natural Sciences, “Babes-Bolyai” University, Fantanele Str. 30, 400294 Cluj-Napoca, Romania
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