Du Xiaoyue, Cai Hongxin, Jin Nan, Wu Zhiguo, Wang Lele, Wang Zeyu, Xie Baogang
Jiaxing University Master Degree Cultivation Base, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
Medical College of Jiaxing University, Key Laboratory of Medical Electronics and Digital Health of Zhejiang Province, Jiaxing University, Jiaxing, China.
Front Pharmacol. 2023 Jul 28;14:1140849. doi: 10.3389/fphar.2023.1140849. eCollection 2023.
The aim of this study was to compare the pharmacokinetics and steady-state serum concentrations of lenvatinib in adult and juvenile rats. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed to quantify lenvatinib in the serum and liver of rats. Six juvenile and six adult rats in each group were orally administered with a single dose of 7.0 mg/kg lenvatinib suspension for pharmacokinetics. Another 12 juvenile and adult rats were subjected to oral gavage with 7.0 mg/kg lenvatinib once daily for 5 days. Biofluild samples were pre-treated by protein precipitation and sorafenib was used as the internal standard for UPLC-MS analysis. The pharmacokinetic parameters were estimated by compartment and statistical model. The mRNA expression of CYP3A2 and SLC22A1 in liver of adult and juvenile rats was measured by real-time fluorescence quantitative PCR (RT-qPCR). The UPLC-MS method met the requirements for quantitative analysis of lenvatinib in serum and liver. The pharmacokinetic results showed that the mean retention time (MRT) was 19.64 ± 7.64 h and 126.38 ± 130.18 h, with AUC values of 3.97 ± 0.73 μg‧mL h and 5.95 ± 2.27 μg mL h in adult and juvenile rats, respectively. When comparing adult rats (0.35 ± 0.15 μg/mL) to juvenile rats, no significant differences were observed in steady-state serum lenvatinib (0.32 ± 0.11 μg/mL), but a noteworthy decrease to one-third of steady-state liver lenvatinib was observed after multiple oral doses of lenvatinib in juvenile rats. Additional findings revealed that the mRNA expression of CYP3A2 and SLC22A1 was notably increased by 6.86 and 14.67 times, respectively, in juvenile rats compared to adult rats. Juvenile rats exhibit lower levels of lenvatinib in the liver's steady-state, potentially due to the disparity in CYP3A2 mRNA expression. These results imply that the dosage of lenvatinib for pediatric patients may need to be augmented in order to attain the desired clinical outcome.
本研究的目的是比较乐伐替尼在成年大鼠和幼年大鼠体内的药代动力学及稳态血清浓度。开发了一种超高效液相色谱 - 质谱联用（UPLC-MS）方法来定量大鼠血清和肝脏中的乐伐替尼。每组6只幼年大鼠和6只成年大鼠口服单剂量7.0mg/kg乐伐替尼混悬液进行药代动力学研究。另外12只幼年和成年大鼠每天经口灌胃7.0mg/kg乐伐替尼，持续5天。生物流体样本通过蛋白沉淀法进行预处理，索拉非尼用作UPLC-MS分析的内标。通过房室和统计模型估算药代动力学参数。采用实时荧光定量PCR（RT-qPCR）检测成年和幼年大鼠肝脏中CYP3A2和SLC22A1的mRNA表达。UPLC-MS方法满足血清和肝脏中乐伐替尼定量分析的要求。药代动力学结果显示，成年大鼠和幼年大鼠的平均保留时间（MRT）分别为19.64±7.64小时和126.38±130.18小时，AUC值分别为3.97±0.73μg‧mL·h和5.95±2.27μg·mL·h。与成年大鼠（0.35±0.15μg/mL）相比，幼年大鼠稳态血清乐伐替尼（0.32±0.11μg/mL）无显著差异，但幼年大鼠多次口服乐伐替尼后，稳态肝脏乐伐替尼显著降至成年大鼠的三分之一。其他研究结果表明，与成年大鼠相比，幼年大鼠肝脏中CYP3A2和SLC22A1的mRNA表达分别显著增加6.86倍和14.67倍。幼年大鼠肝脏稳态时乐伐替尼水平较低，可能是由于CYP3A2 mRNA表达存在差异。这些结果表明，为达到理想的临床效果，可能需要增加儿科患者乐伐替尼的剂量。
