Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes

Abstract

Loteprednol etabonate (LE) is a "soft" steroid belonging to a unique class of glucocorticoids. LE possesses a metabolically labile 17 beta-chloromethyl ester function which was designed in order to be hydrolyzed to an inactive carboxylic acid moiety. The ocular absorption and metabolism of a 14C-labelled LE was evaluated in New-Zealand White rabbits after administration of a 0.5% suspension in both eyes. At various time points following ocular administration, the cornea, aqueous humor, and iris-ciliary body were collected. LE and the putative inactive metabolites, PJ-90 and PJ-91, were identified in all 3 tissues. Levels of LE and its metabolites were highest in the cornea, and so was the ratio of metabolites to unchanged drug, suggesting that the primary site of deactivation of the drug is the corneal tissue. A substantial amount of metabolites were also detected in the iris-ciliary body, although to a lesser extent than in the cornea. The amount of drug and metabolites in the aqueous humor was very low. It is concluded that LE is indeed a soft steroid with good ocular permeation properties.

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

“…The cornea also showed the highest ratio of metabolite to Loteprednol Etabonate (41), indicating that the cornea was the prime site of metabolism, while aqueous humour concentrations of LE were nearly 100-fold lower. This finding suggested that Loteprednol Etabonate may exert a decreased IOP effect as compared to other glucocorticoids [78]. Further a comparison of the IOP-elevating activity of Loteprednol Etabonate with that of Dexamethasone (2) in rabbits confirmed a lack of IOP effect with LE [79,80].…”

“…Loteprednol Etabonate (LE) is predictably metabolized by local esterases into its inactive metabolite Δ 1 -cortienic acid (40) which has been confirmed through animal studies [20]. Clinical studies by Druzgala et al [78] have confirmed that the highest concentration of LE was found in cornea, followed by the iris/ciliary body and aqueous humour. The cornea also showed the highest ratio of metabolite to Loteprednol Etabonate (41), indicating that the cornea was the prime site of metabolism, while aqueous humour concentrations of LE were nearly 100-fold lower.…”

Loteprednol Etabonate 0.5%/Tobramycin 0.3% Compared with Dexamethasone 0.1%/Tobramycin 0.3% for the Treatment of Blepharitis

“…35,36 Previous studies have confirmed the relatively lower risk of IOP elevation with LE compared with other ocular steroids, including studies in known steroid responders. [37][38][39][40][41][42][43][44][45] Limitations of this analysis included the lack of either a non-active control, or a control of a different drug category and the 2-week follow-up period.…”

Retrometabolism‐Based Drug Design and Targeting

“…LE (41) was selected for development based on various considerations including the TI, availability, synthesis, and "softness" (the rate and easiness of metabolic deactivation). Early studies in rabbits [164,167] and rats [168] demonstrated that, consistent with its design, 41 is indeed active, is metabolized into its predicted metabolites (42,43) (Fig. 12), and these metabolites are inactive [163].…”

“…A number of them maintained high binding affinity at the benzodiazepine receptor (<50 nM), showed good (>100-fold) separation of activity between the (active) ester and the (inactive) acid, and were able to cause loss of the righting reflex (LRR) in rats, an effect associated with benzodiazepine full agonism. Structures such as CNS 7259X (164) [367,369] and CNS 7056 (166) [368,370] (Fig. 37) were selected for development, which has been taken over by CeNeS and later PAION.…”