Karbownik Agnieszka, Szałek Edyta, Sobańska Katarzyna, Połom Wojciech, Grabowski Tomasz, Biczysko-Murawa Anna, Matuszewski Marcin, Wolc Anna, Grześkowiak Edmund
Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, ul. Św. Marii Magdaleny 14, 61-861, Poznan, Poland,
Eur J Drug Metab Pharmacokinet. 2015 Jun;40(2):163-70. doi: 10.1007/s13318-014-0191-z. Epub 2014 Mar 28.
The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0-t , AUC0-∞ , and C max and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 μg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean t max of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean t max of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.
该研究旨在考察舒尼替尼对静脉注射对乙酰氨基酚及其主要代谢产物对乙酰氨基酚葡萄糖醛酸苷血浆暴露量的影响。两种药物在肝脏中共享代谢途径，且有报道称舒尼替尼与高剂量对乙酰氨基酚之间存在药物相互作用，这些相互作用会导致肝毒性。成年新西兰雄性兔被分为三组（每组6只）：接受舒尼替尼和对乙酰氨基酚的兔（SUN + PC）、接受舒尼替尼的兔（SUN）以及接受对乙酰氨基酚的对照组（PC）。舒尼替尼口服给药（25 mg），对乙酰氨基酚静脉给药（35 mg/kg）。给药后长达96小时采集用于舒尼替尼和SU12662测定的血样，给药后长达300分钟采集用于对乙酰氨基酚和对乙酰氨基酚葡萄糖醛酸苷测定的血样。在给药前后分析天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和胆红素。分析了一些药代动力学参数。在两个时间点，各组之间的AST、ALT和胆红素水平均无差异。与SUN + PC组相比，PC组对乙酰氨基酚的AUC0-t、AUC0-∞和Cmax值显著更高，清除率和分布容积更低（p < 0.01）。对乙酰氨基酚葡萄糖醛酸苷的最大血浆浓度在PC组中倾向于更高，为213.27 μg/mL（90% CI 1.06, 1.25；p = 0.0267）。对乙酰氨基酚葡萄糖醛酸苷的平均驻留时间（MRT）存在统计学显著差异；SUN + PC组的MRT高于PC组（p = 0.0375）。对乙酰氨基酚葡萄糖醛酸苷的平均tmax在两组（SUN + PC组和PC组）中相似（分别为15分钟和20分钟）。舒尼替尼的平均tmax在SUN + PC组和SUN组中不同（分别为10.0和7.0；p = 0.0134）。在所研究的剂量下，两种药物单独或联合给药均无肝毒性作用。本研究未能证实低剂量舒尼替尼与对乙酰氨基酚联合给药具有肝保护作用。对乙酰氨基酚的一些药代动力学参数存在显著差异。
