Correlation of amikacin concentrations in perilymph and plasma of continuously infused guinea pigs

Abstract

A commercially available radioimmunoassay kit was modified to enable us to measure, in triplicate, the amikacin concentration in 1 ,ld of perilymph fluid. Amikacin levels in plasma and perilymph were measured in guinea pigs after continuous intravenous infusion at four different dosing rates. After a 4-h infusion, a good linear correlation was found between the amikacin concentration in plasma and the dosing rate. Likewise, a significant linear relationship was found between concentrations of amikacin In perilymph and plasma (y = 0.21x + 2.56; r = 0.67; n = 45) after 6 h of infusion. These results suggest nonsaturation kinetics at the concentrations used.The specific toxic effect of aminoglycoside antibiotics (AGs) on the inner ear is related to the fact that they penetrate the inner ear fluid compartments and cause hair cell damage (5,8). Although the rate of entry of AGs into the perilymph space is relatively slow (1, 2, 6, 11), drug levels are prolonged owing to their slow elimination from the inner ear. Different authors have reported widely variable rates of elimination (3 to 15 h) for different AGs (10). As discussed by Manuel et al. (6), intervals between AG doses of less than four half-lives will lead to a notable accumulation in the perilymnph until an equilibrium condition is established. Some authors have suggested the existence of a toxic threshold in the inner ear, meaning that beyond a certain dose the kinetics of AGs are modified and that the concentration increases suddenly in the perilymph (9). Others found a good linear correlation between the dose and perilymph concentrations (3, 4, 6, 10). Pharmacokinetic differences among AGs, as well as differences in the animal species investigated, dose, route of drug administration, time interval between doses, time of sampling, and the analytical technique used, may explain the conflicting conclusions.Amikacin is a semisynthetic derivative of kanamycin and is often used clinically for infections that are resistant to gentamicin or tobramycin. tion of the percentage of relative binding versus the log of the standard concentrations. Logit, probit, and arcsin transformations were tried, and the latter was found to give the best linearity. The rest of the procedure was done according to the protocol provided with the kit. The reproducibility of the assay was assessed by determining the intraassay and interassay coefficients of variation for triplicate determination. Intraassay coefficients of variation ranged from 7.1% for the lowest standard concentrations (5 ng/ml) (n = 10) to 1.8% for the highest standard concentration (320 ng/ml) (n = 10). Two piasma samples with amikacin concentrations of 26.5 and 111.0 ng/ml were measured in triplicate in 12 different assays. Coefficients of variation between assays were found to be 7.2 and 3.7%, respectively.The recovery of drug in 1-plA samples was tested for known concentrations of 4, 9.6, 12.5, and 32 pig/ml with dilution factors Of 1/90, 1/120, 1/250, and 1/500, respectively. The technique described below for per...

Systemic aminoglycosides are trafficked via endolymph into cochlear hair cells

“…This dose was derived from the perilymph-to-serum aminoglycoside ratio of 20% after a 6-hour i.v. infusion9, and likely higher than GTTR levels in perilymph 30 minutes after systemic injection7. After 30 minutes, there was negligible GTTR fluorescence in the stria vascularis and weak fluorescence in hair cells (Fig.…”

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs

“…We assumed that the concentration of amikacin would increase at the same rate and would therefore reach the same level after infusion for 6 h in both ears since previous studies (4,5) found no statistical difference between the amikacin concentrations of both ears. Although blood contamination during perilymph sampling cannot be completely discounted as a possible cause for the higher concentration of amikacin measured in the multiply sampled ear, it is unlikely to be an important factor since minor blood contamination of the perilymph would have been easily observed.…”

“…Since the perilymph compartment is both small and poorly accessible, generally only a single data point can be obtained from each animal (3,15). We recently modified a radioimmunoassay technique so that only 1 ,ul of perilymph sample is required (4). This small size made multiple sampling of the perilymph feasible in an anesthetized animal.…”

“…DISCUSSION In this study we evaluated the possibility of using a multiple-sampling procedure to study the kinetics of am-E 100-~~4 z so-* / ikacin in perilymph. Although the analytical technique for the measurement of amikacin in a 1-pu sample was not a limiting problem (4), it was necessary to determine the possible effects of multiple sampling and prolonged anesthesia on amikacin kinetics.…”

“…We (4) 16.6 ± 4.5 (5) 4 h 11.8 ± 6.7 (5) 23.8 ± 8.3 (6) 35.9 ± 15.2 (6) 6 h 11.1 ± 6.9 (5) 36.8 ± 10.9 (6) 85.0 ± 31.5 (4) Singly solutions were prepared as described above and diluted 10 times with lactate Ringer solution. The pumping rate was then adjusted to 1.25 ml/h to ensure the maintenance of proper fluid levels.…”