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The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

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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...