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研究生:黃靖婷
研究生(外文):Ching Ting, Huang
論文名稱:Dextromethorphan及Dextrorphan經玻璃體內注射給藥之眼部藥物動力學
論文名稱(外文):Ocular pharmacokinetics of dextromethorphan and dextrorphan following intravitreous administration
指導教授:江樵熹江樵熹引用關係
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:85
中文關鍵詞: 內注射給藥 玻璃體 偵測器 動力學 藥動學
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本論文以具神經保護潛能之N-methyl-D-aspartate(NMDA)拮抗劑 Dextromethorphan(DXM)與Dextrorphan(DXO)為研究藥物,使用紐西蘭大白兔為實驗動物,探討DXM與DXO之眼部藥物動力學;經玻璃體內注射給藥,以HPLC分析玻璃體液、房水液及視網膜組織藥物濃度,應用藥物動力學參數評估藥物之眼部分佈情況。
本研究所建立的DXM及DXO之眼組織濃度高效液相層析法分析條件如下。分析管柱 Inertsil® C8-3 (5μm, 4.6 mm x 250 mm);移動相為50 mM potassium dihydrogenphosphate、 acetonitrile、 tetrahydrofuran(比例 75 : 25 : 0.1)三者所組成。使用螢光偵測器,激發及放射波長分別為227 nm及308 nm。移動相之流速為1.0 ml/min,內標準品為Ethylmorphine。Ethylmorphine、DXO與DXM之滯留時間分別為3.9 min、5.2 min及14.8 min。此分析法在0.01~ 0.6 μg/ml範圍有良好線性關係。
以玻璃體內注射給藥,DXM或DXO之劑量為25 μg(2.5 mg/mL, 10 µL),於各特定時間點犧牲動物取樣。可測得玻璃體液、房水液及視網膜組織藥物濃度。再藉由藥物動力學公式,計算各藥動學參數,包括分佈體積(Vd)、清除率(Cl)及AUC。
DXM及DXO之玻璃體液藥物濃度之經時變化。二者之最高濃度皆於15 min分別為21.78±3.35及26.16±1.86 μg/mL,具分佈及排除相之藥動學特性。DXO於視網膜組織上可觀察到有很明顯吸收相與排除相。DXM與DXO於玻璃體內之分布體積及終端排除半衰期分別為2.17±0.61及0.47±0.15 mL和1.49±0.21及0.58±0.12 h。DXM有較大分佈體積及較長之半生期,可能與DXM之脂溶性較高有關。玻璃體內之清除率DXM及DXO分別為0.91±0.16及0.50±0.06 ml/hr,玻璃體內的DXM之清除率大於DXO,與一般較高極性之藥物有較大之清除率不同。DXO於玻璃體液之AUC0-8為52.78±6.03 μg.hr /mL、視網膜AUC0-8為15.88±1.23 μg.hr/g,DXM於玻璃體液及視網膜中之AUC0-8分別為30.70±5.18 μg.hr /mL及33.37±3.25 μg.hr/g。兩藥物在眼組織之分佈情形,有很大差異。
In the study, the analytical method of high performance chromatography(HPLC) was established to determine potential neuroprotective agents, N-methyl-D-aspartate(NMDA) antagonist-dextromethorphan(DXM)and dextrorphan(DXO)levels in vitreous, aqueous and retina following intravitreal injection in New Zealand white rabbits. Ocular pharmacokinetics of DXM and DXO were determined to evaluate the distribution of both drugs in ocular tissues.
The condition of the established HPLC method for analyzing ocular tissue levels of DXM and DXO was described as followings. Mobile phase consisted of 0.05 M potassium dihydrogenphosphate, acetonitrile and tetrahydrofuran with a ratio of 75: 25: 0.1(v/v). The HPLC system was equipped with a pump, a fluorescence detector and an autosampler, with a 50 μL loop injector. A reverse phase C8 column was used to analyze the sample, the flow rate was set at 1 mL/min and run at room temperature. The detector was set at 227 and 308 nm for excitation and emission, respectively. Internal standard was ethylmorphine (EM). The HPLC retention times of EM, DXO and DXM were 3.9, 5.2 and 14.8 min, respectively. The analytical method had good linearity in a range of 0.01~0.6 μg/mL for both drugs.
Rabbits were intravitreally injected with a single dose of 25 μg(2.5 mg/mL, 10μL) either DXO or DXM. At previously set time points, rabbits were sacrificed by intravenous injection of an overdose of sodium pentobarbital, samples of vitreous, aqueous humor and retina were prepared and analyzed by the developed HPLC method. Pharmacokinetic parameters including apparent volume distribution, clearance and AUC were determined.
The time courses of DXM and DXO in vitreous showed two phases of decline with the same peak time at 15 min associated with concentrations 21.78±3.35 μg/mL for DXM and 26.16±1.86 μg/mL for DXO. The apparent volume distributions and terminal elimination half-lives of DXM and DXO, determined from vitreous samples were 2.17±0.61 and 0.47±0.15 mL, as well as 1.49±0.21 and 0.58±0.12 hr, respectively. DXM had a significant higher Vd which was widely distributed in ocular-tissues. DXM also had a higher clearance than that of DXO (0.91±0.16 mL/hr vs 0.50±0.06 mL/hr) in vitreous. The AUC0~8 of vitreous and retina were 52.78±6.03 and 15.88±1.23 μg.hr/g for DXO and 30.70±5.18 and 33.37±3.25 μg.hr/g for DXM. These pharmacokinetic parameters suggested both drugs had different distributive characteristics in ocular tissues that might be further investigated.
第一章、緒論 1
壹、 研究背景 1
貳、 眼球的構造 2
參、 青光眼之簡介 11
一、 青光眼視神經病變之病理生理機制 12
二、 麩氨酸(Glutamate)對神經元之神經興奮性毒性 14
肆、 視神經保護劑 17
一、 DXM之物理化學性質 17
二、 DXM之藥理作用 18
三、 DXM之藥物動力學 19
四、 DXM與DXO之相關研究 19
伍、 玻璃體內藥動學 21
陸、 新穎眼部給藥途徑-玻璃體內注射法 23
柒、 研究目的 24
第二章、材料與方法 25
壹、 材料 25
一、實驗動物 25
二、藥品與試劑 25
三、儀器 26
貳、 研究方法 28
一、 動物實驗操作依據: 28
二、 DXM與DXO之玻璃體液藥動學 28
三、 玻璃體液、房水液及視網膜檢品之取得 32
四、 活體玻璃體液DXM與DXO濃度之分析 33
五、 活體房水液之DXM與DXO濃度之分析 35
六、 分析活體內視網膜之DXM濃度 35
七、 視網膜濃度表示法 35
第三章、結果 37
壹、 DXM與DXO於玻璃體內之藥物動力學 37
一、 DXM與DXO於玻璃體內之HPLC分析圖譜 37
二、 玻璃體內DXM與DXO濃度之檢量線 42
三、 玻璃體內DXM與DXO濃度之經時變化 68
四、 DXM與DXO玻璃體內藥物動力學 68
第四章、討論 72
第五章、結論 75
第六章、參考文獻 76
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