中文摘要 茶鹼(Theophylline)是一種在臨床上控制氣喘的藥物，由於治療指數狹窄，且在體內過程受個體差異及環境因數的影響很大，而有持續釋放錠的發展，由之可以產生更穩定與較長的作用。在本研究中，主要在評估國產持續釋放錠(Theolin SR®)與對照標準品(Euphyllin retard®)在國人的相對生體可用率及兩種定量法(HPLC與FPIA)的分析結果。 12位健康受試者接受此兩種產品的隨機雙向交叉研究，每人每12小時口服單劑量250mg，連續六天，只在第一及第六天抽全程血液檢品。血漿中茶鹼濃度以高效液相層析法(HPLC)定量條件為RP-18e逆相層析管柱、移動相為氰甲烷：磷酸-水(pH 3.88) = 6:94 (v/v)、UV偵測波長272 nm，同樣的檢品也以螢光偏極免疫法(FPIA)分析。兩種分析方法皆有良好的線性關係，其同日、異日精確性及定量極限之變異係數均在10%以內，相對回收率亦大於95%。 結果顯示，茶鹼持續釋放錠在國人第一次口服後約9.8小時可達到最高血中濃度約4.1 μg/ml，平均半衰期(T1/2)約為8.2小時。評估兩種藥品達穩定狀態的藥物動力學參數，包括穩定狀態給藥間隔之曲線下面積(AUCssτ)、達最高血中濃度時間(Tssmax)、最高血中濃度(Cssmax)、最低血中濃度(Cssmin)、平均血中濃度(Cssavg)、血中濃度波動(PTF%)等參數，經由統計學二向變異數分析(Two-way ANOVA)結果，並無顯著的差異，兩藥品是生體相等性的。對於血漿中茶鹼濃度定量法的比較，血漿檢品濃度之相關係數高達0.99以上，分析結果之藥物動力學參數經成對t-檢定。兩種定量法測定同一藥物所得之AUCssτ、Cssmax、Cssmin、Clss/F藥物動力學參數，仍然具有統計學上的差異。; Abstract The theophylline is a drug for controlling asthma in clinical therapy. Since the therapeutic range is relatively narrow and the process in body is influenced by individual and environmental factors very much. Therefore development of sustained release formulation can provide more stable theophylline concentration and long action of the drug. In this study, it was mainly estimating relative bioavailability in Taiwanian and the analysis results of two quantitative methods (HPLC and FPIA) of the sustained release formulations of test preparation (Theolin SR®) and reference preparation (Euphyllin retard®). Twelve healthy subjects received both products by randomized two-way crossover design. Within six days, each subject was administrated 250mg doses every 12 hour. The plasma samples were collected all day only on the first and sixth day. The concentrations of theophylline in plasma samples were analyzed by high performance liquid chromatography (HPLC) system. The conditions of the system were RP-18e column, acetonitril: water with phosphoric acid (pH 3.88) = 6:94 (v/v) and monitored at UV 272 nm. The same samples were also analyzed by fluorescence polarization immunoassay (FPIA) method. These methods showed good linearity, the intra- and inter-day validation and limit of quantification were reasonably with C.V. values less than 10%. The relative recovery was above 95%. The results showed Taiwanian reaching peak concentration (4.1 μg/ml) at about 9.8 hours after first oral administration of theophylline sustained release tablet. The mean half-life was about 8.2 hr. Estimation of steady-state pharmacokinetics parameters of two products were included area under the curve of dose interval (AUCssτ), time of peak concentration (Tssmax), peak concentration (Cssmax), trough concentration (Cssmin), average concentration (Cssavg), fluctuation (PTF%) and so on. After analyzed by two-way ANOVA statistics, there was no obviously statistic difference in relative parameters. Both of products were well bioequivalence by biological. With regard to comparison of two quantitative methods, the correlation of plasma samples concentration was up to 0.99. The results parameters were analyzed by paired t-test, the same drug product was analyzed by two quantitative methods still have obviously statistic different in AUCssτ, Cssmax, Cssmin, Clss/F relative pharmacokinetics parameters.
