Systemic and ocular pharmacokinetics of N-4-benzoylaminophenylsulfonylglycine (BAPSG), a novel aldose reductase inhibitor

Abstract

To better develop N- [4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and selective aldose reductase inhibitor capable of delaying the progression of ocular diabetic complications, the objective of this study was to assess its pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of administration and its distribution to various tissues including those of the eye was studied following intraperitoneal administration. In addition, rat plasma protein binding of BAPSG was studied using ultracentrifugation method and its ocular tissue disposition was assessed following topical administration in rabbits. Plasma and tissue levels of BAPSG were analysed using an HPLC assay. BAPSG exhibited dose-proportionate AUC 0→∞ (area under the plasma HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript concentration-time curve) following both intravenous and intraperitoneal administration over the dose range (5-50 mg kg −1 ) studied and an erratic oral absorption profile with low oral bioavailability. The fraction bioavailability following oral and intraperitoneal administration was 0.06 and 0.7-1, respectively. BAPSG exhibited short plasma elimination half-lives in the range 0.5-1.5 h. BAPSG was bound to rat plasma proteins and the percent protein binding ranged from 83 to 99.8%. BAPSG was better distributed to cornea, lens and retina than to brain, following intraperitoneal administration in rats. However, the distribution was lower compared with kidney and liver. Following topical administration in rabbits, BAPSG delivery to the surface ocular tissues, cornea and conjunctiva was higher compared with intraocular tissues, aqueous humour, iris-ciliary body and lens. Thus, BAPSG was distributed to ocular tissues following systemic and topical modes of administration.

Probenecid treatment enhances retinal and brain delivery of N-4-benzoylaminophenylsulfonylglycine: An anionic aldose reductase inhibitor

“…In this study we observed that intraperitoneal administration of BAPSG after pretreatment with probenecid results in plasma BAPSG exposure (AUC 0–4hr ) of 18.2 µg-hr/ml compared to 21.7 µg-hr/ml reported previously in the absence of probenecid pretreatment (15). Thus, following intraperitoneal administration, similar BAPSG exposure was evident in the plasma with or without probenecid pretreatment.…”

“…In control animals, peak BAPSG levels were observed at 1 hr after dosing in all the ocular tissues except in brain (15), where BAPSG was undetectable beyond 15 min. Following pre-treatment with probenecid, retinal delivery of BAPSG at 1 hr increased by about 11-fold (2.58 vs. 0.24 µg/gm; p<0.05) (Figure 1).…”

“…Probenecid treatments performed as described above in rat and rabbit models were compared with plain drug treatments at the same drug doses reported by our group in a previous study (15). …”

“…Plasma and tissue samples were analyzed using a HPLC assay as per the methods described previously (15). The lower limit of quantification (LOQ) of the assay was 25 ng/ml and the limit of detection (LOD) was 1 ng.…”

Recent Advances in Ophthalmic Drug Delivery

“…In addition, evidence exists for efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the ocular barriers [47,77–80]. Delivery of an anionic aldose reductase inhibitor to cultured human retinal pigment epithelial cells [13], as well as neural retina in vivo in a rat model [13], was elevated by probenecid treatment. This may be an outcome of drug efflux inhibition from eye tissues by probenecid.…”