Dexamethasone Pharmacokinetics in Guinea Pig Inner Ear Perilymph

Abstract

Aim: To study the dexamethasone pharmacokinetics in the inner ear perilymph of guinea pigs using high-pressure liquid chromatography. Methods: Sixty-five guinea pigs were divided into three groups. In the first group, the drug application protocol used an intra-abdominal dose of 0.5% dexamethasone 4 mg·kg^–1. In the second group, an intratympanic application dose of 0.5% dexamethasone 150 µl was used. The third group was the control group. The concentrations of dexamethasone in inner ear perilymph were determined by high-pressure liquid chromatography. Results: The perilymph concentration-time curves of dexamethasone conformed to a one-compartment open model after an intra-abdominal application. The C_maxwas 0.927 ± 0.008 mg·l^–1, the T_max1.47 ± 0.04 h, the T_1/2K 2.92 ± 0.056 h, the AUC 5.533 ± 0.05 mg·h·l^–1, the T_1/2Ka 0.47 ± 0.024 h. After an intratympanic application, the perilymph concentration-time curves of dexamethasone also conformed to a one-compartment open model. The C_maxwas 0.201 ± 0.006 mg·l^–1, the T_max 0.117 ± 0.06 h, the AUC 0.868 ± 0.004 mg·h·l^–1, the T_1/2K 2.918 ± 0.089 h, the T_1/2Ka 0.161 ± 0.009 h. Compared to the intra-abdominal application, the intratympanic application resulted in similar levels of inner ear perilymph drug concentrations in 30 min. Conclusion: Dexamethasone can penetrate the blood-labyrinthine barrier after intra-abdominal application. Dexamethasone can enter into perilymph after intratympanic application. Under the condition of the study, the intratympanic application resulted in a similar level of inner ear perilymph drug concentrations compared to the intra-abdominal application in 30 min.

Immunosuppressive Therapy for Autoimmune Inner Ear Disease

“…In addition, these investigators found that based on plasma levels, intratympanic dexamethasone injections did not result in significant systemic absorption. Similar results were obtained by others measuring perilymph steroid concentrations following systemic versus local administration [59,60]. Collectively, these pharmacokinetic studies show that the limited permeability of the blood–labyrinth barrier prevents systemic absorption of medications delivered to the inner ear by intratympanic injections and that the unique properties of the round window can be exploited for effective targeted drug delivery to the inner ear.…”

Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

“…There have been numerous pharmacokinetic studies of locally-applied corticosteroids in animals (Nomura 1984;Parnes et al 1999;Chandrasekhar et al 2000;Bachmann et al 2001;Hahn et al 2006Hahn et al , 2012Liu et al 2006;Plontke et al 2008b;Yang et al 2008;Wang et al 2009;Borden et al 2011;Salt et al 2011a) and humans (Bird et al 2007;Bird et al 2011), but only a subset of these studies has been analyzed quantitatively to derive an elimination rate. Plontke and analyzed prednisoline data of Bachmann et al (2001) from guinea pigs and found it to be consistent with an elimination half-time from perilymph of 130 min.…”

Pharmacokinetics of Dexamethasone Solution following Intratympanic Injection in Guinea Pig and Sheep

“…These algorithms are based on the current knowledge of inner ear fluid dynamics and aim at developing reliable prediction from animal studies. Other investigators have used more traditional approaches by performing pharmacokinetic studies in rodents [Chandrasekhar et al, 2000;Chen et al, 2006;Liu et al, 2006;Paulson et al, 2008;Wang et al, 2009]. These studies, while interesting, are of limited value with regard to projecting the inner ear disposition of drug substances in humans.…”