Anion efflux transporters are expected to minimize target tissue delivery of N-[4-(benzoylaminophenyl)sulfonyl]
glycine (
BAPSG), a novel
carboxylic acid aldose reductase inhibitor, which exists as a monocarboxylate
anion at physiological conditions. Therefore, the objective of this study was to determine whether
BAPSG delivery to various eye tissues including the retina and the brain can be enhanced by
probenecid, a competitive inhibitor of
anion transporters. To determine the influence of
probenecid on eye and brain distribution of
BAPSG,
probenecid was administered intraperitoneally (120 mg/kg
body weight; i.p.) 20 min prior to
BAPSG (50 mg/kg; i.p.) administration.
Drug disposition in various eye tissues including the retina and the brain was determined at 15 min, 1, 2 and 4h after
BAPSG dose in male Sprauge-Dawley rats. To determine whether
probenecid alters plasma clearance of
BAPSG, influence of
probenecid (120 mg/kg; i.p.) on the plasma pharmacokinetics of intravenously administered
BAPSG (15 mg/kg) was studied as well. Finally, the effect of
probenecid co-administration on the ocular tissue distribution of
BAPSG was assessed in rabbits following topical (
eye drop) administration. Following pretreatment with
probenecid in the rat study,
retinal delivery at 1h was increased by about 11-fold (2580 ng/g vs. 244 ng/g; p<0.05). Further, following
probenecid pretreatment, significant
BAPSG levels were detectable in the brain (45 + or - 20 ng/g) at 1h, unlike controls where the
drug was not detectable. Plasma concentrations, plasma elimination half-life, and total body clearance of intravenously administered
BAPSG were not altered by i.p.
probenecid pretreatment. In the topical dosing study, a significant decline in
BAPSG delivery was observed in the iris-ciliary body but no significant changes were observed in other tissues of the anterior segment of the eye including tears. Thus, inhibition of
anion transporters is a useful approach to elevate
retinal and brain delivery of
BAPSG.