Gao Jinglin, Ren Huan, Feng Zhangying, Chen Shanshan, Liang Yu, Liu Wanqiu, Zhou Qian, Wang Mingxia
Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Xenobiotica. 2020 Sep;50(9):1115-1120. doi: 10.1080/00498254.2020.1740952. Epub 2020 Mar 19.
Apatinib, a small molecule anti-angiogenic tyrosine kinase inhibitor is used extensively to treat advanced gastric cancer and simvastatin (SV) is often co-prescribed to treat cardiovascular disease in cancer patients. As both apatinib and SV are metabolized primarily by cytochrome P450 variant CYP3A4, they are likely to interact. Therefore, the potential effect of SV co-administration on pharmacokinetics of apatinib in Sprague-Dawley male rats is demonstrated for the first time.Sixteen rats were randomly divided into two groups ( = 8), 2 mg/kg SV orally co-administrated for seven days (group B) and the corresponding control group (group A). Apatinib concentrations of rat plasma samples were detected by ultra-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using non compartmental methods.Co-administration of SV for seven days significantly increased area under curve (AUC), AUC and maximum plasma concentration of apatinib by 2.4-, 2.4-, and 2.7-fold, respectively while decreasing apparent volume of distribution and clearance by 81.7 and 73.9%, respectively.These findings suggest that concomitant administration of SV with 7 days may have inhibited the metabolism of apatinib in rats.
阿帕替尼是一种小分子抗血管生成酪氨酸激酶抑制剂，广泛用于治疗晚期胃癌，而辛伐他汀（SV）常与阿帕替尼联合用于治疗癌症患者的心血管疾病。由于阿帕替尼和SV主要通过细胞色素P450变体CYP3A4代谢，它们可能会相互作用。因此，首次证明了SV联合给药对阿帕替尼在Sprague-Dawley雄性大鼠体内药代动力学的潜在影响。将16只大鼠随机分为两组（每组n = 8），一组口服2 mg/kg SV，共给药7天（B组），另一组为相应的对照组（A组）。采用超高效液相色谱串联质谱法检测大鼠血浆样本中的阿帕替尼浓度。使用非房室模型方法计算药代动力学参数。连续7天联合使用SV显著增加了阿帕替尼的曲线下面积（AUC）、AUC和最大血浆浓度，分别增加了2.4倍、2.4倍和2.7倍，同时分别降低了表观分布容积和清除率81.7%和73.9%。这些研究结果表明，连续7天联合使用SV可能抑制了大鼠体内阿帕替尼的代谢。
