Comparison of Drug Availability in the Inner Ear After Oral, Transtympanic, and Combined Administration

Abstract

Although combination of oral and transtympanic drug therapy (CT) has been proved more effective and safer for idiopathic sudden sensorineural hearing loss (ISSNHL) by some clinical trials, there are few laboratory researches on the pharmacokinetics in the inner ear following CT on account of structural limitations of the inner ear. The aim of the present study was to investigate the pharmacokinetic behaviors of CT in the inner ear of mice. Eighteen transgenic GFAP-Luc mice which express luciferase in cochlear spiral ganglion cells were divided into oral administration (OR) group, transtympanic injection route (TT) group and CT group, and luciferin was delivered into the inner ear of these mice through oral, transtympanic or combined routes, respectively. A new in vivo imaging system was used to observe luciferin/luciferase signals and the compare the pharmacokinetics of different administration routes in the inner ear of mice. Bioluminescence signals were observed in the inner ear 3.3 ± 2.6 min after CT, significantly earlier than that of OR group (15.8 ± 7.4 min). CT owned the longest reaching-peak time and largest area under the curve (AUC) among three groups. Compared to TT, CT had longer biological half-life and higher AUC value, but did not displayed stronger peak value. There were significant differences in the peak values between OR group and TT group and between OR group and CT group. This study suggests that the OR route is less effective than the TT or CT route, and combination of OR and TT can deliver more drugs into the inner ear and confer a longer therapeutic window, but cannot increase drug intensity.

Keywords: bioluminescence imaging; drug delivery system; inner ear; mouse; pharmacokinetics.

Figure 1

Photon bioluminescence over time course in GFAP-Luc mice given luciferin. Time course showing photon bioluminescence in the inner ears of mice in oral administration (OR), transtympanic administration (TT), and combined therapy (CT) groups.

Figure 2

Time-dependent changes in photon counts of GFAP-Luc mice administered luciferin via different routes. Error bars indicate standard errors.

Figure 3

Time to inner-ear, time-to-peak of photon count (T_max), and biological half-life (T_1/2) of D-luciferin in the inner ear. (A) Time at which photon count appeared in the inner ear in each group; (B) T_max of D-luciferin was detected in each group. (C) T_1/2. Data represent means ± SE. The bar graph shows the average value of the mice in each group, and the error bar indicates the standard deviation. *P < 0.05.

Figure 4

Peak photon count and the area under the curve (AUC) of D-luciferin in the left inner ear of each group of mice. (A) Peak photon; (B) AUC. The bar graph shows the average value of mice in each group, and the error bars indicate the standard deviation. *P < 0.05.