PO.ET07.02 · 实验与分子治疗

奈必洛尔与达沙替尼在 4T1 三阴性乳腺癌模型中的药代动力学与生物分布评价：对药物-药物相互作用的意义

Pharmacokinetic and biodistribution evaluation of nebivolol and dasatinib in the 4T1 triple-negative breast cancer model: Implications for drug-drug interaction

编号 3158 展板 26 时间 4/20 02:00–05:00 区域 Section 18 主讲 Airong Li, BS;MS;PhD

分会场 Pharmacogenomics and Translational Biomarkers for Precision Cancer Therapy

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作者与单位 Authors & Affiliations

Airong Li¹, Mikayla Skillman², Junhyoung Park³, Fatima Dagher², Amir M. Gholizadeh², Emanuel Baltrip², Meghana Trivedi², Benny A. Kaipparettu³, Diana S.-L. Chow²

¹College of Pharmacy, University of Houston, Houston, TX,²University of Houston, College of Pharmacy, Houston, TX,³Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

摘要 Abstract

中文摘要

背景：在我们近期的体外研究中，奈必洛尔（NEB）与达沙替尼（DAS）协同抑制了 4T1 细胞系的生长，该细胞系是一种用于研究三阴性乳腺癌（TNBC）的小鼠乳腺癌细胞系。然而，其体内处置及潜在的药物-药物相互作用（DDI）尚未明确界定。本研究旨在表征 NEB 与 DAS 在 4T1 荷瘤小鼠体内的药代动力学（PK）与生物分布，并评价联合给药是否改变血浆或组织浓度。方法：雌性 BALB/c 小鼠（7-8 周龄）原位植入 4T1 细胞，分别接受 NEB（n=5）、DAS（n=5）或 NEB+DAS（n=6）治疗。给药方案为 NEB 10 mg/kg 每日一次，DAS 20 mg/kg 每日两次，每周 5 天，持续 3 周。末次给药后，在多个时间点采集血液，并在实验结束时采集组织（肿瘤、肝、肾、肺、脾、心、胰腺和脑）。药物浓度采用经验证的 LC-MS/MS 方法定量。PK 参数由 Phoenix（8.5.1）生成，PK 曲线和统计分析由 GraphPad 10 生成。结果：联合给药显著提高了 NEB 在血液中的暴露量，其曲线下面积（按剂量归一化的 AUC）为 229.45±150.98 hr*ng/mL/(mg/kg)，而单用 NEB 组为 44.51±10.21 hr*ng/mL/(mg/kg)（p<0.05）。NEB 清除率从 24.06±7.13 降至 5.59±2.88 L/(kg*hr)（p<0.05）。联合组与单用 DAS 组相比，DAS 的浓度和参数未见显著改变。生物分布分析显示联合组的组织分配发生了改变。联合组所有组织中 NEB 浓度均高于单用 NEB 组（因方差较大，p>0.05）。组织-血液（T/B）比值反映了药物的组织摄取情况。两种药物在肿瘤、肝、肺、脾、肾和胰腺中的 T/B 比值均大于 1，表明存在优先的组织蓄积。尽管单用 NEB 组（32.27±61.87）和单用 DAS 组（99.45±179.53）肿瘤中的 T/B 比值高于联合组（分别为 2.53±2.25、3.73±2.41），但因方差较大未观察到显著差异，提示联合给药可影响瘤内递送。联合给药下 DAS 在肾脏中的 T/B 比值较单用 DAS 显著升高，表明联合治疗中 DAS 在肾脏的蓄积增多。结论：联合给药导致 NEB 在血液中暴露量升高、清除率降低，并使 DAS 的肾脏分布增加。分布的变化提示存在药物-药物相互作用。这些发现为机制性 PK/PD 建模提供了基础框架，并支持进一步研究 NEB+DAS 联合治疗 TNBC。

查看英文原文 English abstract

Background: In our recent in-vitro study, nebivolol (NEB) and dasatinib (DAS) synergistically inhibited the growth of 4T1 cell line, which is a murine mammary carcinoma cell line used to study triple-negative breast cancer (TNBC). However, the in vivo disposition and potential for drug-drug interactions (DDI) are not well defined. This study aimed to characterize the pharmacokinetics (PK) and biodistribution of NEB and DAS in 4T1 tumor-bearing mice and evaluate whether co-administration modifies plasma or tissue concentrations. Methods: Female BALB/c mice (7-8 weeks) were implanted with 4T1 cells orthotopically and treated with NEB (n=5), DAS (n=5), or NEB+DAS (n=6). The regimen was NEB 10 mg/kg once a day and DAS 20 mg/kg twice a day, 5 days/week for 3 weeks. After the last dose, blood was collected at multiple time points and tissues (tumor, liver, kidney, lung, spleen, heart, pancreas, and brain) were harvested at the end. Drug concentration was quantified using a validated LC-MS/MS method. PK parameters were generated by Phoenix (8.5.1) and GraphPad 10 was used to generate the PK profile and statistical analysis. Results: Co-administration significantly increased NEB exposure in blood, of which the area under curve (AUC normalized by dose) was 229.45±150.98 hr*ng/mL/(mg/kg), compared to 44.51±10.21 hr*ng/mL/(mg/kg) in the NEB alone group (p<0.05). The NEB clearance was decreased from 24.06±7.13 to 5.59±2.88 L/(kg*hr) (p<0.05). DAS concentration and parameters were not changed significantly in combination group vs. DAS alone group. Biodistribution analysis modified tissue partitioning in the combination group. NEB concentrations in all tissues were higher in combination group than NEB alone group (p>0.05 due to the large variance). Tissue-to-blood (T/B) ratios interpreted the tissue uptake of drugs. T/B ratios of both drugs in tumor, liver, lung, spleen, kidney and pancreas were over 1, indicating preferential tissue accumulation. Even though the T/B ratios in tumor were higher in NEB (32.27±61.87) and DAS (99.45±179.53) alone groups than the combination group (2.53±2.25, 3.73±2.41, respectively), no significant difference was observed due to the large variance, suggesting that co-administration can influence intratumoral delivery. The ratio (T/B) of DAS in the kidney was significantly elevated under combination dosing compared with DAS alone, which indicated more DAS accumulation in combination treatment. Conclusions: Combination dosing led to a higher exposure of NEB in blood with a lower clearance, and an increased renal distribution of DAS. Distribution shifts indicated a drug-drug interaction. These findings provide a foundational framework for mechanistic PK/PD modeling and support further investigation of NEB+DAS combination for TNBC treatment.

利益披露 Disclosure

A. Li, None.. M. Skillman, None.. J. Park, None.. F. Dagher, None.. A. M. Gholizadeh, None.. E. Baltrip, None.. M. Trivedi, None.. B. A. Kaipparettu, None.. D. S. Chow, None.

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