Sakai Tatsuya, Shinno Keisuke, Kurata Masaaki, Kawamura Akio
Research and Development Division, Senju Pharmaceutical Co., Ltd., Osaka, Japan.
Ophthalmol Ther. 2019 Dec;8(4):511-517. doi: 10.1007/s40123-019-00205-0. Epub 2019 Aug 1.
Azithromycin demonstrates high tissue distribution and prolonged elimination half-life. In this study, we monitored the pharmacokinetics of a single ophthalmic administration of 1% azithromycin ophthalmic solution containing polycarbophil in the extraocular tissues, including the eyelid, and compared it with that of two commercial ophthalmic products, 1.5% levofloxacin ophthalmic solution and 0.3% ofloxacin ophthalmic ointment.
Rabbits were treated with either a single topical administration of 1% azithromycin ophthalmic solution, 1.5% levofloxacin ophthalmic solution, or 0.3% ofloxacin ophthalmic ointment. The eyelid, conjunctiva, and cornea were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h post-administration. Tissue samples were pretreated for drug concentration measurements by ultra-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by non-compartmental analysis.
Azithromycin was rapidly absorbed, and its levels remained near the observed maximum concentrations for up to 24 h post-administration in all tissue. In contrast, extraocular tissue concentrations of levofloxacin and ofloxacin decreased with time. The maximum concentrations of azithromycin, levofloxacin, and ofloxacin were 35.6, 34.1, and 55.1 µg/g in the eyelid, 44.2, 46.8, and 20.4 µg/g in the conjunctiva, and 79.9, 18.0, and 2.21 µg/g in the cornea, respectively. The values of the area under the curve from 0 to 24 h after administration of azithromycin, levofloxacin, and ofloxacin were 602, 58.5, and 267 µg·h/g in the eyelid, 837, 43.2, and 51.9 µg·h/g in the conjunctiva, and 1250, 26.4, and 5.46 µg h/g in the cornea, respectively.
The drug concentrations of azithromycin and levofloxacin were relatively comparable among the extraocular tissues following topical administration of the respective ophthalmic solutions, whereas the concentrations of ofloxacin varied following dosing of its ophthalmic ointment. The slow elimination profile in any extraocular tissue of rabbits was unique to azithromycin, and led to the demonstration of high exposures of azithromycin in all extraocular tissues after ophthalmic administration.
This research and Rapid Service Fees were supported by Senju Pharmaceutical Co., Ltd.
阿奇霉素具有较高的组织分布和较长的消除半衰期。在本研究中，我们监测了单次眼部给药含聚卡波非的1%阿奇霉素滴眼液在眼外组织（包括眼睑）中的药代动力学，并将其与两种市售眼科产品（1.5%左氧氟沙星滴眼液和0.3%氧氟沙星眼膏）进行比较。
对兔子分别单次局部给予1%阿奇霉素滴眼液、1.5%左氧氟沙星滴眼液或0.3%氧氟沙星眼膏。给药后0.25、0.5、1、2、4、8和24小时收集眼睑、结膜和角膜。通过超高效液相色谱-串联质谱法对组织样本进行预处理以测量药物浓度。通过非房室分析确定药代动力学参数。
阿奇霉素吸收迅速，给药后24小时内其在所有组织中的水平均保持在接近观察到的最大浓度。相比之下，左氧氟沙星和氧氟沙星的眼外组织浓度随时间降低。阿奇霉素、左氧氟沙星和氧氟沙星在眼睑中的最大浓度分别为35.6、34.1和55.1μg/g，在结膜中分别为44.2、46.8和20.4μg/g，在角膜中分别为79.9、18.0和2.21μg/g。阿奇霉素、左氧氟沙星和氧氟沙星给药后0至24小时的曲线下面积值在眼睑中分别为602、58.5和267μg·h/g，在结膜中分别为837、43.2和51.9μg·h/g，在角膜中分别为1250、26.4和5.46μg·h/g。
局部给予各自的眼科溶液后，阿奇霉素和左氧氟沙星在眼外组织中的药物浓度相对可比，而氧氟沙星眼膏给药后其浓度有所不同。阿奇霉素在兔子任何眼外组织中的缓慢消除特征是其独有的，导致眼部给药后阿奇霉素在所有眼外组织中的暴露量较高。
本研究及快速服务费由参天制药株式会社提供支持。
