title: Competitive antagonism of fluorescent gentamicin uptake in the cochlea.
abstract: Aminoglycosides enter inner ear hair cells via apical endocytosis, or mechanoelectrical transduction channels, implying that, in vivo, aminoglycosides enter hair cells from endolymph prior to exerting their cytotoxic effect. If so, circulating aminoglycosides likely cross the strial blood-labyrinth barrier and enter marginal cells prior to clearance into endolymph. We characterized the competitive antagonism of unconjugated aminoglycosides on the uptake of fluorescent gentamicin (GTTR) in the stria vascularis and kidney cells at an early time point. In mice, uptake of GTTR by kidney proximal tubule cells was competitively antagonized by gentamicin at all doses, but only weakly by kanamycin (mimicking in vitro data). GTTR fluorescence was approximately 100-fold greater in proximal tubule cells than in the stria vascularis. Furthermore, only high molar ratios of aminoglycosides significantly reduced strial uptake of GTTR. Thus, gentamicin antagonism of GTTR uptake is more efficacious in proximal tubules than in the stria vascularis. Competitive antagonism of GTTR uptake is indicative of specific cell-regulatable uptake mechanisms (e.g., ion channels, transporters) in the kidney. Strial uptake mechanisms have lower specific affinity for gentamicin, and/or density (compared to the kidney), yet may be critical to transport gentamicin across the strial blood-labyrinth barrier into marginal cells.
authors.affiliation: Oregon Hearing Research Center, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Allan
authors.initials: A
authors.lastname: Kachelmeier
authors.forename: P S
authors.initials: PS
authors.lastname: Steyger
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002460:Cell Line; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005839:Gentamicins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007612:Kanamycin / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D013316:Stria Vascularis / Q000187:drug effects / Q000378:metabolism; D014966:Xanthenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000617:Aminoglycosides; D005456:Fluorescent Dyes; D005839:Gentamicins; D014966:Xanthenes; D007612:Kanamycin; C034657:Texas red