Effect of isepamicin dosing scheme on concentration in cochlear tissue

To investigate the possible effect of the dosing scheme of aminoglycosides on their concentration in the cochlear tissue, we gave two groups of 12 guinea pigs subcutaneous doses of 45 mg of isepamicin (ca. 30 mg of active product) per kg of body weight daily for eight consecutive days. The first group received the drug by continuous infusion, while the second group received it by single daily injection. On the final day of administration, the animals were sacrificed and the cochlear tissue was removed. The tissues from the cochleas of pairs of guinea pigs were pooled. The isepamicin concentrations in the cochlear duct tissue (organ of Corti plus lateral wall) and the cochlear nerve tissue were determined separately. Hearing levels before and after treatment were assessed by means of frequency-specific auditory brain stem responses (ABR). The creatinine level in serum was determined on the last day of the administration. None of the animals in either group showed signs of renal insufficiency or of hearing impairment. The median isepamicin concentration in the cochlear duct was 2.40 micrograms/mg of protein after continuous administration and 2.50 micrograms/mg of protein after once-daily administration, compared with the concentration in the cochlear nerve, where it was 1.93 micrograms/mg of protein after continuous administration and 2.59 micrograms/mg of protein after once-daily administration. These differences are statistically insignificant. The results give evidence for linear uptake kinetics of isepamicin in the inner ear tissue and may be directly relevant to the clinical dosing of the drug.