Department of Pharmacy, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, 200233 Shanghai, China; School of Pharmacy, Shanghai Jiao Tong University, 200240 Shanghai, China.
Toxicol Appl Pharmacol. 2013 Oct 1;272(1):238-44. doi: 10.1016/j.taap.2013.06.002. Epub 2013 Jun 14.
Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague-Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5mg/kg) alone, and DOX co-administrated with either 20 or 40mg/kg nilotinib. Blood was withdrawn at 12 time points till 72h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC-MS-MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section was carried out to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40mg/kg nilotinib increased the AUC0-t and Cmax of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased serum exposure, but significantly decreased the accumulation of DOX in cardiac tissue. Consistent with in vitro profile, oral dose of 40mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing P-gp activity in the heart.
多柔比星（DOX）是一种具有较窄治疗窗的有效化疗药物。尼罗替尼是一种小分子 Bcr-Abl 酪氨酸激酶抑制剂，据报道其可以逆转 P 糖蛋白（P-gp）跨膜转运蛋白介导的多药耐药（MDR）。本研究旨在探讨尼罗替尼对多柔比星（DOX）稳态药代动力学、分布和心脏毒性的影响。将 24 只雄性 Sprague-Dawley 大鼠随机分为 4 组（每组 6 只），分别给予以下方案：生理盐水、静脉注射 DOX（5mg/kg）单独用药，以及 DOX 联合 20 或 40mg/kg 尼罗替尼用药。在 DOX 注射后 12 个时间点采集血液，直至 72h，并采用 LC-MS-MS 法测定血清和心肌组织中 DOX 及其代谢产物多柔比星醇（DOXol）的浓度。为了确定心脏毒性，检测了肌酸激酶、乳酸脱氢酶、丙二醛和超氧化物歧化酶。对心脏切片进行组织病理学检查，以评估治疗后心脏毒性的严重程度。结果显示，预先给予 40mg/kg 尼罗替尼增加了 DOX 和 DOXol 的 AUC0-t 和 Cmax。然而，与单独给予 DOX 的组相比，它们在心肌组织中的积累显著减少。此外，生化和组织病理学结果表明，40mg/kg 尼罗替尼减轻了 DOX 给药引起的心脏毒性。总之，尼罗替尼联合用药增加了血清暴露量，但显著降低了 DOX 在心肌组织中的积累。与体外研究结果一致，口服 40mg/kg 尼罗替尼通过增强心脏中的 P-gp 活性，显著降低了 DOX 在大鼠中的心脏毒性。
