Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, Sw. Marii Magdaleny 14, PL 61-861 Poznań, Poland.
Pharmacol Rep. 2013;65(5):1383-90. doi: 10.1016/s1734-1140(13)71497-x.
Fluoroquinolones are widely prescribed antibiotics. Ciprofloxacin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for levofloxacin and moxifloxacin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib which is indicated for the treatment of gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC). This study investigated the effects of single intravenous dose of ciprofloxacin, levofloxacin or moxifloxacin on the pharmacokinetics of sunitinib.
Rabbits were subjected to one of four study drug groups: sunitinib + ciprofloxacin (n = 6), sunitinib + levofloxacin (n = 6), sunitinib + moxifloxacin (n = 6), or sunitinib alone (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. The antibiotics were administered intravenously at the doses of 20, 25 and 20 mg/kg, respectively. Plasma concentrations of sunitinib and active metabolite (SU12662) were measured with validated HPLC method with UV detection.
The comparison of sunitinib Cmax for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 1.81 (90% CI 1.33, 2.44), 1.59 (90% CI 1.18, 2.16), 1.06 (90% CI 0.79, 1.44), respectively. The comparison of sunitinib AUC0-∞ for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 2.90 (90% CI 1.32, 6.37), 2.45 (1.11, 5.39), 1.58 (0.70, 1.56), respectively. The mean sunitinib tmax was similar for all four groups. The mean Cmax for SU12662 was similar for both the sunitinib + moxifloxacin and sunitinib groups (p = 0.9593). However, the mean Cmax for SU12662 for the groups: sunitinib + ciprofloxacin and sunitinib + levofloxacin were higher (p = 0.0045 and 0.0672, respectively).
The study proved a significant effect of the coadministration of ciprofloxacin and levofloxacin on the pharmacokinetics of sunitinib in rabbits. The influence of moxifloxacin on the pharmacokinetics of sunitinib was insignificant. Therefore, this fluoroquinolone seems to be the most appropriate in combination with this tyrosine kinase inhibitor.
氟喹诺酮类药物被广泛用作抗生素。环丙沙星是一种众所周知的细胞色素 P450 CYP3A4 抑制剂，会引起许多药物相互作用，而左氧氟沙星和莫西沙星则没有这些作用。CYP3A4 参与新的口服多激酶抑制剂舒尼替尼的代谢，舒尼替尼适用于胃肠道间质瘤（GIST）和晚期肾细胞癌（RCC）的治疗。本研究旨在研究单次静脉给予环丙沙星、左氧氟沙星或莫西沙星对舒尼替尼药代动力学的影响。
将兔子分为四组中的一组：舒尼替尼+环丙沙星（n = 6）、舒尼替尼+左氧氟沙星（n = 6）、舒尼替尼+莫西沙星（n = 6）或舒尼替尼单药组（n = 6）。兔子以 25 mg 的口服剂量接受舒尼替尼治疗。抗生素分别以 20、25 和 20 mg/kg 的剂量静脉给药。采用经验证的 HPLC 法（UV 检测）测定舒尼替尼和活性代谢物（SU12662）的血浆浓度。
舒尼替尼+环丙沙星、舒尼替尼+左氧氟沙星、舒尼替尼+莫西沙星组与舒尼替尼组的舒尼替尼 Cmax 比较比值分别为 1.81（90%CI 1.33，2.44）、1.59（90%CI 1.18，2.16）、1.06（90%CI 0.79，1.44）。舒尼替尼+环丙沙星、舒尼替尼+左氧氟沙星、舒尼替尼+莫西沙星组与舒尼替尼组的舒尼替尼 AUC0-∞ 比较比值分别为 2.90（90%CI 1.32，6.37）、2.45（1.11，5.39）、1.58（0.70，1.56）。四组舒尼替尼 tmax 均值相似。舒尼替尼+莫西沙星组和舒尼替尼组的 SU12662 平均 Cmax 相似（p = 0.9593）。然而，舒尼替尼+环丙沙星组和舒尼替尼+左氧氟沙星组的 SU12662 平均 Cmax 更高（p = 0.0045 和 0.0672）。
本研究证明了环丙沙星和左氧氟沙星联合应用对兔体内舒尼替尼药代动力学的显著影响。莫西沙星对舒尼替尼药代动力学的影响不显著。因此，这种氟喹诺酮类药物与这种酪氨酸激酶抑制剂联合应用似乎最为合适。
