title: In vivo evaluation of 11beta-hydroxysteroid dehydrogenase activity in the rabbit eye.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pfizer Global R&D La Jolla, San Diego, CA 92121, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Anderson
authors.forename: Samantha
authors.initials: S
authors.lastname: Carreiro
authors.forename: Terri
authors.initials: T
authors.lastname: Quenzer
authors.forename: David
authors.initials: D
authors.lastname: Gale
authors.forename: Cathie
authors.initials: C
authors.lastname: Xiang
authors.forename: Hovhannes
authors.initials: H
authors.lastname: Gukasyan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lafontaine
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Achim
authors.initials: A
authors.lastname: Krauss
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry; D002853:Chromatography, Liquid; D003348:Cortisone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006854:Hydrocortisone / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D011817:Rabbits; D053719:Tandem Mass Spectrometry
chemical_list: D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D006854:Hydrocortisone