Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.
Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.
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DOI：
10.3389/fvets.2023.1297221
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发表时间：
2023
影响因子：
3.2
通讯作者：
Thippeswamy, Thimmasettappa
中科院分区：
文献类型：
--
作者：
Vasanthi, Suraj S.;Massey, Nyzil;Nair, Suresh N.;Mochel, Jonathan P.;Showman, Lucas;Thippeswamy, Thimmasettappa
Saracatinib/AZD 0530（SAR）是一种Src酪氨酸激酶抑制剂，在癫痫模型中重复经口给药后可减轻癫痫诱导的脑病理学。然而，重复给药是有压力的，在一些癫痫发作的动物中可能具有挑战性。为了克服这个问题，我们将SAR纳入饮食中，并将血清药代动力学（PK）和脑浓度与常规重复口服给药进行比较。溶液或饮食中的Saracatinib在室温下稳定>4周（97 ± 1.56%）。与常规饲料相比，SAR饲料中的成年Sprague道利大鼠摄食量减少约1.7 g/天（16.82 ± 0.6 g/天vs. 18.50 ± 0.5 g/天），但体重增加/天未受影响（2.63 ± 0.5 g/天vs. 2.83 ± 0.2 g/天）。重要的是，我们分别获得了2.5-18.7 mg/kg大鼠的预期SAR剂量范围，以响应54 - 260 ppm饲料中不同浓度的SAR。饲料中SAR剂量（mg/kg）与血清saracatinib浓度（ng/ml）之间存在强烈且显着的相关性。SAR饮食中给药和重复经口给药之间的血清浓度也无显著差异。来自SAR饮食中给药的海马体saracatinib浓度高于重复经口给药后的浓度（第3天，546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g;第7天，300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g）。Saracatinib在室温下的稳定性以及饲喂SAR饲料的动物中的高血清和海马浓度可用于滴定未来动物疾病模型的Saracatinib剂量。总的来说，饮食中的测试药物是一种实验方法，解决了动物实验中处理压力诱导变量的相关问题。
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.
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影响因子：
3.1
作者：
Gucalp A;Sparano JA;Caravelli J;Santamauro J;Patil S;Abbruzzi A;Pellegrino C;Bromberg J;Dang C;Theodoulou M;Massague J;Norton L;Hudis C;Traina TA
通讯作者：
Traina TA
影响因子：
4.6
作者：
通讯作者：
--
影响因子：
5.3
作者：
Gage M;Putra M;Gomez-Estrada C;Golden M;Wachter L;Gard M;Thippeswamy T
通讯作者：
Thippeswamy T
影响因子：
11.2
作者：
Kaufman, Adam C.;Salazar, Santiago V.;Haas, Laura T.;Yang, Jinhee;Kostylev, Mikhail A.;Jeng, Amanda T.;Robinson, Sophie A.;Gunther, Erik C.;van Dyck, Christopher H.;Nygaard, Haakon B.;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.
IB期在阿尔茨海默氏病中的AZD0530（Saracatinib）的安全性，耐受性和中枢神经系统可用性的多次升级剂量研究。
DOI：
10.1186/s13195-015-0119-0
发表时间：
2015
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Nygaard HB;Wagner AF;Bowen GS;Good SP;MacAvoy MG;Strittmatter KA;Kaufman AC;Rosenberg BJ;Sekine-Konno T;Varma P;Chen K;Koleske AJ;Reiman EM;Strittmatter SM;van Dyck CH
通讯作者：
van Dyck CH