Anderson Scott, Carreiro Samantha, Quenzer Terri, Gale David, Xiang Cathie, Gukasyan Hovhannes, Lafontaine Jennifer, Cheng Hengmiao, Krauss Achim, Prasanna Ganesh
Pfizer Global R&D La Jolla, San Diego, CA 92121, USA.
J Ocul Pharmacol Ther. 2009 Jun;25(3):215-22. doi: 10.1089/jop.2008.0120.
Steroids are used in a diverse range of conditions in clinical ophthalmology and one of the most significant complications is corticosteroid-induced glaucoma, which is characterized by an increase in intraocular pressure (IOP). 11beta-Hydroxysteroid dehydrogenase-1 (11beta-HSD1) is known to catalyze the interconversion of hormonally inactive cortisone to hormonally active cortisol and is widely expressed in the eye, particularly ciliary epithelium. Carbenoxolone (CBX), an 11beta-HSD1 inhibitor, has been shown to reduce IOP in healthy volunteers and patients with ocular hypertension (OHT). The purpose of this study was to: (1) develop an in vivo model for the assessment of cortisone to cortisol conversion in the eye, that is, 11beta-HSD1 activity and (2) assess the pharmacokinetic/pharmacodynamic relationship following topical treatment with 11beta-HSD1 inhibitors using an in vivo rabbit model.
Potent and selective 11beta-HSD1 inhibitors were topically administered to the rabbit eye and exogenous cortisone to endogenous cortisol conversion in the eye was assessed in rabbits. Tissues were then evaluated for cortisone, cortisol, and 11beta-HSD1 inhibitor levels by LC/MS/MS. Concomitantly cortisol activity in ocular tissue samples was determined using a secondary mechanistic pLuc-GRE assay.
Topical treatment with potent and selective 11beta-HSD1 inhibitors resulted in complete inhibition in the conversion of cortisone to cortisol in the rabbit eye as well as decreased pLuc-GRE luciferase activity. The reduction of cortisone conversion was time- and dose-dependent as well as dependent on dosing volume (suggestive of increased spillover and washout with greater dosing volume).
In conclusion, topical delivery of 11beta-HSD1 inhibitors can reduce or inhibit the conversion of cortisone to cortisol in the eye, indicating that the rabbit eye possesses an active enzyme for glucocorticoid synthesis. Dosing concentration and volume play an important role in the pharmacokinetic and pharmacodynamic effects of topically delivering an 11beta-HSD1 inhibitor. The rabbit model is useful for mechanistically assessing the conversion of cortisone to cortisol in the eye.
类固醇在临床眼科的多种病症中都有应用，其中最严重的并发症之一是皮质类固醇性青光眼，其特征是眼压（IOP）升高。已知11β-羟基类固醇脱氢酶-1（11β-HSD1）可催化无激素活性的可的松向有激素活性的皮质醇的相互转化，且在眼中广泛表达，尤其是在睫状体上皮中。生胃酮（CBX）是一种11β-HSD1抑制剂，已被证明可降低健康志愿者和高眼压症（OHT）患者的眼压。本研究的目的是：（1）建立一种体内模型，用于评估眼中可的松向皮质醇的转化，即11β-HSD1活性；（2）使用体内兔模型评估局部应用11β-HSD1抑制剂后的药代动力学/药效学关系。
将强效且选择性的11β-HSD1抑制剂局部应用于兔眼，并评估兔眼中外源性可的松向内源性皮质醇的转化。然后通过液相色谱/串联质谱法（LC/MS/MS）评估组织中的可的松、皮质醇和11β-HSD1抑制剂水平。同时，使用二级机制pLuc-GRE测定法测定眼组织样本中的皮质醇活性。
局部应用强效且选择性的11β-HSD1抑制剂可导致兔眼中可的松向皮质醇的转化完全受到抑制，同时pLuc-GRE荧光素酶活性降低。可的松转化的降低具有时间和剂量依赖性，并且还取决于给药体积（提示给药体积越大，溢出和清除增加）。
总之，局部应用11β-HSD1抑制剂可减少或抑制眼中可的松向皮质醇的转化，表明兔眼具有一种用于糖皮质激素合成的活性酶。给药浓度和体积在局部应用11β-HSD1抑制剂的药代动力学和药效学效应中起重要作用。兔模型对于从机制上评估眼中可的松向皮质醇的转化很有用。
