Abstract
Purpose :
Intravitreal delivery of non-steroidal anti-inflammatory (NSAID) drugs remains problematic due to their short half-life in the vitreous. Further understanding of their intraocular pharmacokinetics could be particularly beneficial for many retinopathies that have an inflammatory component. Flurbiprofen,a widely used NSAID, is pharmaceutically available as a racemate. Racemates are consisted of an equimolar mixture of two enantiomers, which have the same chemical structure; however, they exhibit significant biological differences. The purpose of this study was to evaluate the pharmacokinetics of flurbiprofen, administered intravitreally in rats, with chiral and non-chiral analysis.
Methods :
Flurbiprofen (10 μg) was administered intravitreally in Sprague-Dawley rats and animals were euthanized 0,1, 24 and 168 hours post injection. Vitreous sampling was achieved through the optic nerve. Due to technical difficulties to isolate vitreous from the rat, the analysis was also performed in whole-eye samples. Both vitreous and homogenized whole-eye samples were analyzed through chiral and non-chiral columns of LC-MS.
Results :
Flurbiprofen was detected in the vitreous samples in a maximum concentration of 75,23 μg/ml (0 hours) with an immense clearance of 88% 1-hour post injection and a 92.6% recovery. In whole-eye samples, maximum concentration was 32,4 μg/gr (0 hours) while it was significantly reduced to 4,5 μg/gr 1-hour post injection and 0,5 μg/gr at 24 hours (it was below detection at 168 hours) with an 88,3% recovery. In whole-eye samples, half-life of flurbiprofen was 80 minutes with an elimination constant rate (Ke) of 0,87. Chiral analysis at 0 hours, detected one isomer in a maximum concentration of 17,10 μg/gr and the other one at a maximum concentration of 17,78 μg/gr. Both enantiomers’ concentration was 34,88 μg/gr following the maximum concentration at 0 hours with non-chiral analysis.Furthermore, the enantiomers had the same bioavailability and clearance with a half-life of 82 minutes and Ke of 0,84.
Conclusions :
Chiral separation and analysis of flurbiprofen’s racemic mixture revealed that both enantiomers are detected in the eye after intravitreal administration in rats and have almost identical pharmacokinetic profiles. Moreover, they both have the same short half-life, which is significantly shorter than it has been previously reported in other species.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.