在兔子肌肉注射模式中 Levodopa 劑量依存性（Dose-dependence）之藥物動力學研究   全文下載

A Dose-Dependent Pharmacokinetic Study of Levodopa by Intramuscular Administration in Rabbits

本研究為將levodopa 以肌肉注射方式投予家兔，探討levodopa 劑量依存性之藥物動力學。以三種不同劑量的L-dopa/carbidopa（2/0.5, 5/1.25, and 10/2.5 mg/kg）經肌肉注射及一種劑量之L-dopa/carbidopa（2/0.5 mg/kg）經靜脈注射，依交叉試驗方式分別投予六隻雄性兔子，在投藥後採血，取血漿樣品並以高壓液相層析儀分析L-dopa 及3-O-methyldopa （levodopa 之代謝物， 3-OMD）之濃度，經由所得之數據決定L-dopa 與3-OMD 之藥物動力學之模式。由結果得知，L-dopa 經肌肉注射後會被快速吸收，並於30 分鐘內達到最高濃度，但3-OMD 的形成則較慢，須於120-180 分後才達到最高點。L-dopa 經肌肉注射後之生體可用率為0.70-1.21，而3-OMD 形成之相對比率為 0.79-1.24；另於不同劑量間，L-dopa 之肌肉注射生體可用率及3-OMD 形成比率不具統計上的差異。此外，L-dopa 與3-OMD 於排除半衰期上也不具統計上的差異；而在曲線下面積（AUC）及血漿中最高濃度值（Cmax），L-dopa 與3-OMD 於L-dopa/carbidopa 在2/0.5-10/2.5 mg/kg 劑量範圍內亦呈現正比增加之現象。由此可知，L-dopa 與3-OMD 在此劑量範圍內無劑量依存性之藥物動力學現象。"

The dose-dependent pharmacokinetics of levodopa (L-dopa) was studied in rabbits by intramuscular administration. Three different doses of L-dopa/carbidopa (2/0.5, 5/1.25, and 10/2.5 mg/kg) were administered to six male rabbits via an intramuscular (IM) route, and one dose of L-dopa/carbidopa (2/0.5 mg/kg) was administered via an intravenous (IV) route with a washout period of 1-week between different doses. Plasma samples were collected after each treatment and the concentrations of L-dopa and 3- O-methyldopa (an L-dopa metabolite, 3-OMD) were measured by a sensitive high-performance liquid chromatographic (HPLC) method. Subsequently, these measurements were used to determine the pharmacokinetic behavior of L-dopa and 3-OMD. The results indicated that the absorption of L-dopa was fast with the time to the peak within 30 min, but the formation of 3-OMD was slow with the time to the peak of 120-180 min after IM administration. The IM bioavailability of L-dopa was in the range of 0.70- 1.21, and the relative ratios of the formation of 3-OMD at different doses of L-dopa were in the range of 0.79-1.24. No statistically significant difference could be observed for IM bioavailability of L-dopa or for the relative ratios of the formation of 3-OMD in this dose range. The elimination half-lives of L-dopa and 3-OMD also exhibited no significant differences for each dose after IM administration. In addition, both the area under the curve (AUC) and maximum plasma concentration (Cmax) values of L-dopa and 3-OMD increased proportionally over the dose range of 2/0.5-10/2.5 mg/kg for L-dopa/carbidopa, suggesting that L-dopa and 3- OMD obeyed dose-independent pharmacokinetics.