Transport, pharmacokinetics and ocular delivery of N-4-[(benzoylamino)phenylsulfonyl]glycine, an aldose reductase inhibitor

Aldose reductase inhibitors (ARIs) are potential therapeutic agents in delaying or preventing ocular diabetic complications such as corneal epitheliopathy, cataract and retinopathy. Previously developed ARIs failed in clinical studies due to their poor target tissue penetration. Thus, the objective of this study was to understand the disposition of novel ARIs and to identify a permeable ARI based on in vitro transport, to assess its in vivo activity and pharmacokinetics, and to investigate approaches to enhance its ocular delivery.; Transport of benzoylaminophenylsulfonylglycines (BAPSGs) and benzoylphenylglycines (BNPGs) across rabbit cornea and conjunctiva was studied in vitro . BAPSG, the lead compound of the BAPSG series, was identified for further studies based on its high permeability/IC₅₀ ratio. BAPSG exhibited ARI activity in rat lens organ cultures and reduced cataract scores in a galactose-fed rat model.; Pharmacokinetic studies found that, in rats, BAPSG exhibited a plasma elimination half-life of 0.6–1 hr with a clearance of 0.68–0.77 L/hr/kg. Following topical administration in rabbits, the tissue distribution of BAPSG measured as AUC_0–3hr was in the order: cornea >> conjunctiva > aqueous humor. In rats, the oral and intraperitoneal bioavailability of BAPSG was 6.5% and 95%, respectively. Following intrapentoneal (i.p.) administration, the tissue AUC_0–4hr, was in the order: kidney >> liver > cornea > heart > spleen > retina >> lens >> brain.; To enhance the ocular delivery of BAPSG, two approaches were utilized. In the first approach, two lipophilic ester prodrugs modifying the -COOH group in BAPSG were synthesized and evaluated for their ocular uptake in a rabbit model. In vivo uptake and in vitro permeability of BAPSG were greater than those of the prodrugs, suggesting the importance of -COOH in topical delivery of BAPSG. Additional transport studies indicated that BAPSG is likely transported across the cornea by a carrier-mediated process. In the second approach, BAPSG was administered (50 mg/kg, i.p.) following pre-treatment with probenecid (125 mg/kg, i.p.), an inhibitor of anionic drug efflux transporter. Probenecid treatment increased the retinal levels of BAPSG by 10-fold, suggesting a role for anionic efflux transporters in limiting the retinal accumulation of BAPSG.; In conclusion, BAPSG, a selective and permeable ARI, reaches intra-ocular tissues and is capable of inhibiting cataract formation. The lipophilic prodrug approach did not enhance topical BAPSG delivery. Pre-treatment with an inhibitor of organic anion efflux transporters may be useful in elevating the retinal delivery of BAPSG following systemic administration.