| Chapter I : Quantitative interpretation of dexamethasone pharmacokinetics ininner ear perilymph using computer simulationsThere is an increasing interest in the treatment of inner ear disorders by application of dexamethasone. For further development and transfer of this promising therapeutic strategy into controlled clinical trials, it is necessary to undergo pharmacokinetic studies to evaluate the therapeutic effects objectively. Direct studies of inner ear pharmacokinetic in humans are not possible, because human inner ear fluids cannot be safely sampled without damage to the ear. The alternative is to predict drug levels from results obtained in animal experiments. To make quantitative predictions, a methodology must be established that is applicable to the unique situation of the inner ear fluids spaces. Computer simulations provide a valuable tool for the interpretation and planning of animal studies, for evaluating changes of application protocols and drug delivery systems, and for extrapolating the results from animal studies to the human.On the study, high-performance liquid chromatography (HPLC) and computer simulations were used to study the dexamethasone pharmacokinetic in inner ear perilymph in guinea pigs and human. In addition, the change of cochlear after intratympanic dexamethasone application has been investigated in this study.Chapter I was divided into three parts: Part I : Quantitative interpretation of dexamethasone pharmacokinetics inguinea pigs inner ear perilymphObjective: To study the dexamethasone pharmacokinetics in guinea pigs inner ear perilymph under different drug administration using high-performance liquid chromatography. To provoid base for clinic therapeutic strategy and provoid objectivedata for computer simulations.Methods: 53 guinea pigs were divided into three groups. Two application protocols were used in the part. The first protocol was an intratympanic application dose of 0.5% dexamethasone 150ul, where the guinea pigs movement was controlled to the extent that the applied drug stayed in contact with the round window membrance for 30 minutes. The second protocol was an intra-abdominal application dose of 0.5% dexamethasone 0.4mg/100g. The inner ear perilymph concentrations and plasma concentrations of dexamethasone were determined by high-performance liquid chromatography in 53 guinea pigs.Result: The perilymph concentration-time curves of dexamethasone were conformed to one compartment open model after an intratympanic application dose of 0.5% dexamethasone 150ulin guinea pigs. The Cmax was 0.201+0.006ug.ml-1, the Tmax was 0.117+0.06 h, the AUC was 0.868+0.004ug h.ml-1, the T1/2K was 2.918+0.089h, the T1/2Ka was 0.161+0.009 h. The plasma concentration was 0ug.ml-1.The perilymph concentration-time curves of dexamethasone were conformed to one compartment open model after an intra-abdominal application dose of 0.5% dexamethasone 0.4mg/100g, The Cmax was 0.927+0.008 ug.ml-1, the Tmax was 1.47+0.04 h, the T1/2K was 2.92+0.056 h, the AUC was 5.533+0.05 ug.h.ml-1, the T1/2Ka was 0.47+0.024 h; The plasma concentration-time curves of dexamethasone were conformed to one compartment open model. The Cmax was 5.595+0.12ug.ml-1, the Tmax was 1.971 +0.03 h, the AUC was 30.44+0.568 ug.h.ml-1, the T1/2K was 1.639+0.06 h, the T1/2Ka Was 1.151 +0.024 h; Conclusion:1. we first reported the dexamethasone pharmacokinetics in inner ear perilymph by high-performance liquid chromatography in guinea pigs.2. Dexamethasone can penetrate the blood-labyrinthine barriers after intra-abdominal application. The perilymph and plasma concentration-time curves of dexamethasone were conformed to one compartment open model. The half life of dexamethasone in inner ear perilymph is 1.8 times than that in plasma.3. Dexamethasone can enter into perilymph after mtratympanic application. The innerear perilymph concentration-time curves of dexamethasone were conformed to onecompartment open model. Dexamethasone enter into inner ear perilymph withoutthrough the route of...
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