Higher drug levels in CSF than in systemic blood following topical ocular administration

Abstract

Purpose: Traditionally, an ocular pharmacokinetic study (PK) includes only one extra-ocular sampling site, which is the systemic blood circulation. This study aims to address the feasibility of including cerebrospinal fluid (CSF) sampling in routine ocular PK studies.

Methods: Albino rabbits were euthanized at 15, 30, 45, 60, 120, 180 and 360 min. following one single topical administration to the right eye of 50 µL of 3H-radiolabeled 0.1% dexamethason solution. Both eyes aqueous-humor and vitreous were sampled as well as systemic blood and CSF, which was aspirated from the Cisterna Magna. Samples were processed for the determination of 3H-dexamethason and the calculation of its ng-equivalent.

Results: C-max (ng/gr), T-max (min.) and AUC (ng x min./gr) were 285.72, 45 and 31003.91 for treated-eye aqueous, 27.65, 30 and 4509.88 for contralateral aqueous, 33.16, 45 and 5945.97 for treated-eye vitreous, 10.87, 30 and 3436.28 for contralateral vitreous, 27.47, 15 and 4942.73 for CSF, and 16.42, 30 and 2837.86 for the systemic blood.

Conclusions: The arterial supply and veinous return of the eye and the orbit are affiliated almost entirely with the intracranial vascular system. The CSF circulation has an orbital extension, up to the retrobulbar optic nerve head. While sampling intracranial blood is a complicated task, CSF sampling via Cisterna Magna is feasible following a relatively short learning curve. The topically administered dexamethason was available in the CSF at concentration levels comparable to the vitreous levels in both eyes and the contralateral eye aqueous-humor levels. Moreover, dexamethason AUC in CSF was 16% of the AUC of treated-eye aqueous and 174% of that in systemic blood circulation. While more insights are needed for the interpretation of the higher drug levels in CSF than in systemic blood following local ocular administration, the results justifies the inclusion of CSF sampling alongside systemic blood sampling in routine ocular PK's.

Keywords: 503 drug toxicity/drug effects • 487 corticosteroids