Individual Variation and Mechanism of Kanamycin Ototoxicity in Rabbits

Previous studies have failed to fully establish whether ototoxicity is related in any way to the levels of an aminoglycoside antibiotic in the perilymph. To study this we exposed guinea pigs to continuously infused amikacin at four different dosing rates under conditions parallel to those used in our previous study which related ototoxicity to total plasma area under the concentration-time curve regardless of the level in plasma. It was found that at all dosing rates, levels in the perilymph and ratios of levels in perilymph/plasma remained constant as the dosing duration increased from nonototoxic to strongly ototoxic. Plasma and perilymph amikacin levels were found to be linear functions of the dosing rate even at ototoxic dosing exposures, and ratios of levels in perilymph/plasma did not differ between dosing rates. The total perilymph area under the concentration-time curve was not different between dosing rates either for a total dose associated with threshold ototoxicity or for one associated with severe ototoxicity. The results suggest that amikacin ototoxicity is related to the integral of the concentration in the perilymph over the total time of amikacin exposure regardless of the level in the perilymph.

Section: Discussionmentioning

confidence: 99%

Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration

Beaubien

Ormsby

Bayne

et al. 1991

“…Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.…”

mentioning

confidence: 99%

“…In the perilymph fluid, however, the concentration of amikacin was not modified by pentobarbital, indicating that factors other than concentration in blood can affect the entry of amikacin into the inner ear. Because the ototoxic potential of aminoglycosides is thought to be related to the drug concentration in the perilymph fluid (1,12,14), a better understanding of factors affecting their transfer from blood to perilymph would help in predicting conditions likely to increase or decrease the ototoxicity of AG.…”

mentioning

confidence: 99%

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

Desjardins-Giasson¹,

Beaubien²,

Cauchy³

1985

The purpose of this study was to determine whether a multiple-sampling procedure could be used in guinea pigs to study the kinetics of amikacin in perilymph. Amikacin was infused intravenously for 6 h into conscious anesthetized guinea pigs, and the concentrations of the drug in plasma and perilymph were measured. From each anesthetized guinea pig, five to six perilymph samples were collected from one ear, and one sample was collected from the other ear at 6 h. The concentrations of amikacin in perilymph were dose proportional and increased slowly during the 6-h infusion. However, after 6 h of intravenous infusion, the concentrations of amikacin in perilymph of the multiply sampled ears were significantly higher than those of the singly sampled ears, indicating that the multiple-sampling procedure should not be used as is to study the kinetics of amikacin in perilymph. Amikacin concentrations in perilymph were linearly related to amikacin concentrations in plasma in pentobarbital-anesthetized animals, as had previously been observed for conscious guinea pigs. However, the slope of the regression line was only 0.09 for anesthetized animals compared with 0.24 for conscious animals. Drug concentrations in plasma were found to be threefold higher in anesthetized animals, whereas drug levels in perilymph were the same in both groups at similar dosing rates. These results indicate that the amikacin concentration in perilymph is not solely dependent upon its concentration in plasma and that other factor(s) can affect the entry of amikacin into the inner ear.Ototoxicity is a well-known adverse effect of aminoglycoside antibiotics (AG). Many investigators believe that the inner ear damage is related to the concentration of AG in the perilymph (1,3,5,8,12,14). Although the rates of entry of AG into perilymph are much slower than those of AG into plasma, these drugs seem to accumulate in the perilymph after repetitive dosing because of their slow elimination rates from this body fluid.Investigators in our laboratory are presently trying to determine the relationship between ototoxicity and the concentrations of amikacin in the perilymph and plasma of guinea pigs. While trying to determine the kinetics of amikacin in perilymph, we wanted to reduce the number of animals required to establish the various rate constants. 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. 350 g were used. Food and water were provided ad libitum. Room temperature (21 to 22°C), humidity (50 to 55%), and light cycle (12 h on, 12 h off) were kept constant throughout the experiment.The control group consisted of 19 conscious guinea pigs which had undergone jugular cannulation 48 h previously. Each animal received one of the following i.v. doses of amikacin for 6...

“…Ohtani et al (7), using doses of 100 and 200 mg of kanamycin per kg, could not find any linear relationship between perilymph and serum drug levels 4 h after the last of 40 or 30 daily intraperitoneal injections. It should be noted, however, that in this case the two dose levels did not produce significantly different serum drug levels (7).…”

Section: Resultsmentioning

confidence: 94%

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

Desjardins-Giasson¹,

Beaubien²

1984

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...