耳后给药及鼓室给药外淋巴液药物浓度的实验观察

Dexamethasone concentration in perilymph following post-aural or intratympanic Injection

目的研究耳后皮下注射给药、鼓室内给药后外淋巴液中地塞米松磷酸钠的药物代谢动力学特征，探讨两种给药途径的药代动力学差异。方法以地塞米松磷酸钠(10mg/ml)为药物示踪剂，将豚鼠随机分为耳后注射（耳后组）和鼓室内给药（鼓室组）2组，耳后组给药量为1ml（10mg/ml），鼓室组给药量为0.1ml（10mg/ml），分别采集耳后组给药0.25、0.5、1、2.5、5、6、8小时外淋巴液及鼓室组给药后0.5、1、2、3、4、6、8小时外淋巴液，用高效液相色谱法分别检测其中的药物浓度。结果①两种方式给药后，豚鼠外淋巴液中均可检测出地塞米松，且浓度均随时间的延长呈下降趋势；②鼓室组：给药后0.5～8h外淋巴液中均可检出有效药物成份地塞米松，3h达峰，其峰浓度（Cmax）最高为906.55mg/l，生物半衰期为1.27h。③耳后组:给药后0.25～8h可检出地塞米松，其达峰时间（Tmax）为0.25h，其峰浓度（Cmax）最高为18.83mg/l，生物半衰期为3.36h。④鼓室组给药量为0.1ml，耳后组给药量为1ml，外淋巴液中鼓室组地塞米松的浓度高于耳后组。⑤耳后组药物半衰期比鼓室给药组高。结论提示耳后皮下注射给药药物可能通过多种途径进入外淋巴，药物浓度相对鼓室给药低；鼓室给药组因避开血脑屏障及血迷路屏障故可较快进入外淋巴，保持较高药物浓度；结合临床我们可推测激素在外淋巴中可能低浓度即可起效。

Objective To compare dexamethasone concentration in the perilymph (PL) after post-aural or intratympanicinjection in guinea pigs. Methods Dexamethasone sodium phosphate (10 mg/ml) was injected post-aurally (1 ml) orintratympanically (0.1 ml) in guinea pigs. Samples of perilymph were obtained at 0.25, 0.5, 1, 2.5, 5, 6 and 8 hours afterpost-aural injection and at 0.5, 1, 2, 3, 4, 6 and 8 hours after intratympanic injection respectively. High-performance liquidchromatography(HPLC)was used to assay dexamethasone concentration in the samples. Results ① dexamethasone was detectedin the inner ear following both modes of injection; ② Following intratympanic injection, active pharmaceutical ingredientswere detected from 0.5 to 8 hours in the perilymph, peaking at 3 hours with a peak concentration (Cmax) of906.55mg/l and a biological half-life of 1.27 hours. ③ After post-aural injection, dexamethasone was detected from 0.25 to8 hours with a peak time (Tmax) at 0.25 hour, a Cmax at 18.83 mg/l and a biological half-life of 3.36 hours. ④ The perilymphdexamethasone concentration was lower but half-life longer after post-aural injection than after intratympanic administration.Conclusion Drugs may enter the perilymph space by various ways after post-aural injection, although drug concentrationmay be relatively lower compared to intratympanic administration. As the intratympanic route bypasses theblood-brain and blood-labyrinth barriers, drugs through this route may gain access into the perilymph faster and reach higherconcentrations than when given via post-aural injection. Clinical observation, however, seems to suggest that onset of corticoidseffects may start at a relatively low concentration in the perilymph.