title: Hydrophilic pyrazine dyes as exogenous fluorescent tracer agents for real-time point-of-care measurement of glomerular filtration rate.
abstract: Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.
authors.affiliation: Covidien Pharmaceuticals, 675 McDonnell Boulevard, Hazelwood, Missouri 63042, USA. Raghavan.Rajagopalan@covidien.com
authors.forename: Raghavan
authors.initials: R
authors.lastname: Rajagopalan
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Amruta R
authors.initials: AR
authors.lastname: Poreddy
authors.forename: Richard M
authors.initials: RM
authors.lastname: Fitch
authors.forename: John N
authors.initials: JN
authors.lastname: Freskos
authors.forename: Bethel
authors.initials: B
authors.lastname: Asmelash
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Gaston
authors.forename: Karen P
authors.initials: KP
authors.lastname: Galen
authors.forename: Jeng-Jong
authors.initials: JJ
authors.lastname: Shieh
authors.forename: Richard B
authors.initials: RB
authors.lastname: Dorshow
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D005919:Glomerular Filtration Rate; D008297:Male; D051379:Mice; D019095:Point-of-Care Systems; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001798:Blood Proteins; D005456:Fluorescent Dyes; D011719:Pyrazines