Liew Ming Hui, Ng Salby, Chew Chii Chii, Koo Teng Wai, Chee Yun Lee, Chee Evelyn Li-Ching, Modamio Pilar, Fernández Cecilia, Mariño Eduardo L, Segarra Ignacio
Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, Kuala Lumpur, Malaysia.
Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avn. Joan XXIII s/n, 08028, Barcelona, Spain.
Invest New Drugs. 2017 Apr;35(2):145-157. doi: 10.1007/s10637-016-0415-y. Epub 2017 Jan 9.
The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC, 31% and 27% lower liver and kidney AUC and 2.2-fold higher AUC in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC (p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.
在雄性和雌性小鼠中评估了酪氨酸激酶抑制剂舒尼替尼与对乙酰氨基酚的性别差异药代动力学及相互作用。给小鼠（对照组）单独口服60mg/kg舒尼替尼或与200mg/kg对乙酰氨基酚联合口服（研究组）。测定血浆、脑、肾和肝脏中的舒尼替尼浓度，并进行非房室药代动力学分析。雌性对照小鼠的血浆舒尼替尼AUC比雄性对照小鼠高36%，肝脏和肾脏AUC分别低31%和27%，脑AUC高2.2倍（均p<0.001），且肝肾与血浆的AUC比值较低（p<0.001）。对乙酰氨基酚使雄性小鼠的血浆AUC降低29%（p<0.05），而雌性小鼠则无变化。在雄性和雌性小鼠中，它分别使肝脏（15%，9%）、肾脏（15%，20%）和脑（47%，50%）的AUC降低（p<0.001），这是由于雌性小鼠脑摄取效率降低了52%（p<0.01）。舒尼替尼表现出性别差异的药代动力学、组织分布和药物相互作用，对脑肿瘤和肾细胞癌患者的治疗具有潜在的临床可转化性。
