Probenecid treatment enhances retinal and brain delivery of N-4-benzoylaminophenylsulfonylglycine: an anionic aldose reductase inhibitor.
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.
Sunkara
Gangadhar
G
University of Colorado Denver, Aurora, CO, USA.
Ayalasomayajula
Surya P
SP
DeRuiter
Jack
J
Kompella
Uday B
UB
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects*; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects
D000277:Adjuvants, Pharmaceutic; D004791:Enzyme Inhibitors; D013450:Sulfones; C062604:N-(((4-benzoylamino)phenyl)sulfonyl)glycine; D011339:Probenecid; D005998:Glycine