Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare
Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compa...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2023.1297221/full |
| _version_ | 1797629745553211392 |
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| author | Suraj S. Vasanthi Nyzil Massey Suresh N. Nair Jonathan P. Mochel Lucas Showman Thimmasettappa Thippeswamy |
| author_facet | Suraj S. Vasanthi Nyzil Massey Suresh N. Nair Jonathan P. Mochel Lucas Showman Thimmasettappa Thippeswamy |
| author_sort | Suraj S. Vasanthi |
| collection | DOAJ |
| description | Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing. Saracatinib in solution or in-diet was stable at room temperature for >4 weeks (97 ± 1.56%). Adult Sprague Dawley rats on SAR-in-Diet consumed ~1.7 g/day less compared to regular diet (16.82 ± 0.6 vs. 18.50 ± 0.5 g/day), but the weight gain/day was unaffected (2.63 ± 0.5 g/day vs. 2.83 ± 0.2 g/day). Importantly, we achieved the anticipated SAR dose range from 2.5–18.7 mg/kg of rat in response to varying concentrations of SAR-in-Diet from 54 to 260 ppm of feed, respectively. There was a strong and significant correlation between SAR-in-Diet dose (mg/kg) and serum saracatinib concentrations (ng/ml). Serum concentrations also did not vary significantly between SAR-in-Diet and repeated oral dosing. The hippocampal saracatinib concentrations derived from SAR-in-Diet treatment were higher than those derived after repeated oral dosing (day 3, 546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g; day 7, 300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g). Saracatinib stability at room temperature and high serum and hippocampal concentrations in animals fed on SAR-in-Diet are useful to titer the saracatinib dose for future animal disease models. Overall, test drugs in the diet is an experimental approach that addresses issues related to handling stress-induced variables in animal experiments. |
| first_indexed | 2024-03-11T10:57:21Z |
| format | Article |
| id | doaj.art-7c514cee98144e1db9ae0052e453e9fa |
| institution | Directory Open Access Journal |
| issn | 2297-1769 |
| language | English |
| last_indexed | 2024-03-11T10:57:21Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj.art-7c514cee98144e1db9ae0052e453e9fa2023-11-13T04:40:32ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692023-11-011010.3389/fvets.2023.12972211297221Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfareSuraj S. Vasanthi0Nyzil Massey1Suresh N. Nair2Jonathan P. Mochel3Lucas Showman4Thimmasettappa Thippeswamy5Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesDepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesDepartment of Veterinary Pharmacology and Toxicology, College of Veterinary and Animal Sciences, Kerala Veterinary and Animal Sciences University, Thrissur, IndiaPrecision One Health, Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, United StatesW.M. Keck Metabolomics Research Laboratory, Iowa State University, Ames, IA, United StatesDepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United StatesSaracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing. Saracatinib in solution or in-diet was stable at room temperature for >4 weeks (97 ± 1.56%). Adult Sprague Dawley rats on SAR-in-Diet consumed ~1.7 g/day less compared to regular diet (16.82 ± 0.6 vs. 18.50 ± 0.5 g/day), but the weight gain/day was unaffected (2.63 ± 0.5 g/day vs. 2.83 ± 0.2 g/day). Importantly, we achieved the anticipated SAR dose range from 2.5–18.7 mg/kg of rat in response to varying concentrations of SAR-in-Diet from 54 to 260 ppm of feed, respectively. There was a strong and significant correlation between SAR-in-Diet dose (mg/kg) and serum saracatinib concentrations (ng/ml). Serum concentrations also did not vary significantly between SAR-in-Diet and repeated oral dosing. The hippocampal saracatinib concentrations derived from SAR-in-Diet treatment were higher than those derived after repeated oral dosing (day 3, 546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g; day 7, 300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g). Saracatinib stability at room temperature and high serum and hippocampal concentrations in animals fed on SAR-in-Diet are useful to titer the saracatinib dose for future animal disease models. Overall, test drugs in the diet is an experimental approach that addresses issues related to handling stress-induced variables in animal experiments.https://www.frontiersin.org/articles/10.3389/fvets.2023.1297221/fullsaracatinibSrc tyrosine kinasesserumLC–MS/MShippocampuspharmacokinetics |
| spellingShingle | Suraj S. Vasanthi Nyzil Massey Suresh N. Nair Jonathan P. Mochel Lucas Showman Thimmasettappa Thippeswamy Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare Frontiers in Veterinary Science saracatinib Src tyrosine kinases serum LC–MS/MS hippocampus pharmacokinetics |
| title | Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare |
| title_full | Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare |
| title_fullStr | Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare |
| title_full_unstemmed | Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare |
| title_short | Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare |
| title_sort | exploring the benefits of in diet versus repeated oral dosing of saracatinib azd0530 in chronic studies insights into pharmacokinetics and animal welfare |
| topic | saracatinib Src tyrosine kinases serum LC–MS/MS hippocampus pharmacokinetics |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2023.1297221/full |
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