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 – 4 hours 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.

Gentamicin delivery to the inner ear: Does endolymphatic hydrops matter?

“…The measuring range of the iGentamicin assay was 0.3–10 μg/ml. The samples were adequately diluted with artificial perilymph (KCl (3.5mM), NaCl (125mM), NaHCO3 (25mM), CaCl2 (1.3mM), MgCl2 (1.2mM), NaH2PO4 (0.75mM), Dextrose (5mM)) [ 18 ] to keep this range, as appropriate. The final perilymphatic concentration was calculated taking into consideration these dilution rates.…”

Inner ear delivery: Challenges and opportunities

“…Some studies suggest that the oval window may even play a larger role than the RWM with inner ear diffusion as higher levels of gadolinium are detected in the scala vestibuli than in the scala tympani after intratympanic administration, and higher levels of chitosan nanoparticles are detected at the stapes footplate compared to the RWM . However, it remains unclear what fraction of inner ear delivery can be attributed to diffusion across the RWM and across the oval window, with other studies suggesting up to 35% diffusion across the oval window …”

Intracochlear drug delivery systems: a novel approach whose time has come

“…Difficult to reach the apex. Drug leakage to CSF via the cochlear aqueduct close to the RWM [28]. Substantially increase drug bioavailability in the inner ear, but may establish a base-to-apex gradient.…”