title: Perilymph pharmacokinetics of locally-applied gentamicin in the guinea pig.
abstract: Intratympanic gentamicin therapy is widely used clinically to suppress the vestibular symptoms of Meniere's disease. Dosing in humans was empirically established and we still know remarkably little about where gentamicin enters the inner ear, where it reaches in the inner ear and what time course it follows after local applications. In this study, gentamicin was applied to the round window niche as a 20 μL bolus of 40 mg/ml solution. Ten 2 μL samples of perilymph were collected sequentially from the lateral semi-circular canal (LSCC) at times from 1 to 4 h after application. Gentamicin concentration was typically highest in samples originating from the vestibule and was lower in samples originating from scala tympani. To interpret these results, perilymph elimination kinetics for gentamicin was quantified by loading the entire perilymph space by injection at the LSCC with a 500 μg/ml gentamicin solution followed by sequential perilymph sampling from the LSCC after different delay times. This allowed concentration decline in perilymph to be followed with time. Gentamicin was retained well in scala vestibuli and the vestibule but declined rapidly at the base of scala tympani, dominated by interactions of perilymph with CSF, as reported for other substances. Quantitative analysis, taking into account perilymph kinetics for gentamicin, showed that more gentamicin entered at the round window membrane (57%) than at the stapes (35%) but the lower concentrations found in scala tympani were due to greater losses there. The gentamicin levels found in perilymph of the vestibule, which are higher than would be expected from round window entry alone, undoubtedly contribute to the vestibulotoxic effects of the drug. Furthermore, calculations of gentamicin distribution following targeted applications to the RW or stapes are more consistent with cochleotoxicity depending on the gentamicin concentration in scala vestibuli rather than that in scala tympani.
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis MO, USA. Electronic address: salta@ent.wustl.edu.
authors.forename: A N
authors.initials: AN
authors.lastname: Salt
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis MO, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Hartsock
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis MO, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Gill
authors.affiliation: Bionics Institute of Australia, Melbourne VIC, Australia.
authors.forename: E
authors.initials: E
authors.lastname: King
authors.affiliation: Zentrallabor, Department of Laboratory Medicine, University Hospital Halle, Ernst Grube Str. 40, 06120 Halle (Saale), Germany.
authors.forename: F B
authors.initials: FB
authors.lastname: Kraus
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Plontke
mesh_terms: D000818:Animals; D005839:Gentamicins / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D006801:Humans; D008575:Meniere Disease / Q000188:drug therapy; D008954:Models, Biological; D010498:Perilymph / Q000378:metabolism*; D012405:Round Window, Ear / Q000378:metabolism; D012533:Scala Tympani / Q000378:metabolism; D012665:Semicircular Canals / Q000378:metabolism; D014722:Vestibule, Labyrinth / Q000378:metabolism
chemical_list: D005839:Gentamicins
keywords: Cochleotoxicity; Distribution; Drug delivery; Elimination; Intratympanic; Permeability; Round window; Stapes