地氟泼尼龙眼用乳剂滴入后兔眼组织中地氟泼尼龙的代谢谱。

Metabolic profiles of difluprednate in rabbit ocular tissues after instillation of difluprednate ophthalmic emulsion.

作者信息

Tajika Tetsuya, Takahashi Hiroaki, Sakai Yusuke, Fujii Hiroyuki, Isowaki Akiharu, Sakaki Hideyuki

机构信息

Preclinical Laboratories, Senju Pharmaceutical Co., Ltd., Kobe, Hyogo, Japan.

出版信息

Xenobiotica. 2010 Aug;40(8):569-77. doi: 10.3109/00498254.2010.490308.

DOI:10.3109/00498254.2010.490308

PMID:20509750

Abstract

Difluprednate (DFBA; 6alpha,9-difluoro-11beta,17,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate 17-butyrate) is an effective anti-inflammatory agent derived from prednisolone. The present study aimed to evaluate the metabolite profile of DFBA in rabbit ocular tissues after instillation of DFBA ophthalmic emulsion. The high-performance liquid chromatography with radiochemical detection was employed to analyze radioactivity in rabbit ocular tissues that had been instilled with a (3)H-DFBA 0.05% ophthalmic emulsion. At 0.5 and 2 h after instillation, DFBA was not detected in the cornea, aqueous humor, or iris/ciliary body. Instead, 21-deacetylated DFBA (DFB), 17-debutylated DFB (DF), and an unknown metabolite were found. The unknown metabolite was identified as de-17-side chain-glucocorticoid metabolite (DF21C), which is a novel glucocorticoid metabolite formed by the scission of the 17-side chain via an unknown metabolic reaction pathway. The K(i) value of DF21C was 5.6 x 10(-7) mol/L, indicating very weak glucocorticoid receptor binding of DF21C (approximately 1000-fold less than that of DFBA and DFB).

摘要

双氟泼尼酯（DFBA；6α,9-二氟-11β,17,21-三羟基-1,4-孕二烯-3,20-二酮21-醋酸酯17-丁酸酯）是一种从泼尼松龙衍生而来的有效抗炎剂。本研究旨在评估DFBA眼用乳剂滴入兔眼组织后的代谢物谱。采用放射化学检测的高效液相色谱法分析用0.05%的(3)H-DFBA眼用乳剂滴注后的兔眼组织中的放射性。滴注后0.5小时和2小时，在角膜、房水或虹膜/睫状体中未检测到DFBA。相反，发现了21-脱乙酰基DFBA（DFB）、17-脱丁酰基DFB（DF）和一种未知代谢物。该未知代谢物被鉴定为去-17-侧链-糖皮质激素代谢物（DF21C），它是一种通过未知代谢反应途径切断17-侧链形成的新型糖皮质激素代谢物。DF21C的K(i)值为5.6×10(-7)mol/L，表明DF21C与糖皮质激素受体的结合非常弱（约比DFBA和DFB低1000倍）。