- 學位論文
以藥物結構特性利用液相層析串聯質譜開發分析血漿中metolazone和fexofenadine濃度方法及藥動研究
Considering the drug structural features to develop methods for metolazone and fexofenadine in human plasma by LC-MS/MS and apply to pharmcokinetic studies
摘要
本研究的目的是利用藥物結構特性，開發出靈敏的液相層析串聯質譜分析方法並用於測量人類血漿中metolazone與fexofenadine濃度。研究藥物的藥物動力學時，分析方法的開發與確效十分重要，而液相層析串聯質譜為實驗室中常用的分析方法，可應用於鑑定及藥物產品、生物檢體中藥物成分的定量分析。本研究系將兩個具有多官能基的藥物成分進行研究。解析藥物結構的官能基與裂解途徑開發出液相層析串聯質譜分析方法。液相層析串聯質譜使用電灑法配合多重反應監測模式偵測。Metolazone的檢量線線性範圍分別為0.02 – 15 ng/mL。回內分析與回間分析品管檢體的變異係數低於6.3%。最低可定量濃度為0.02 ng/mL。於fexofenadine執行分析確效的，內分析與回間分析品管檢體的變異係數低6.7%(最低可定量濃度組為15.4%)。最低可定量濃度為1 ng/mL，可定量濃度至1000 ng/mL具有良好的線性關係。 完成確效的分析方法，成功地應用於測量健康受者口服metolazone或fexofenadine後的人體血漿中的藥物濃度。此項研究工作有助於取得健康受試者經口服給藥後，metolazone和fexofenadine的藥物動力學數據。使用常態分佈分析後，metolazone於健康台灣男性受試者的藥物動力學特性未顯示具有多型性。於分析健康台灣男性受試者fexofenadine的藥物動力學參數後，fexofenadine的曲線下面積經常態分布檢定呈現三群，顯示藥物動力學特性具有三種表現型。三個族群可定義為高吸收/暴露量族群、中等吸收/暴露量族群及低度吸收/暴露量族群，個別族群的平均AUCinf分別為7376 ± 1006, 4731 ± 563 and 2816 ± 568 h×ng/mL。台灣人族群對fexofenadine的吸收可能具有不同的吸收能力。與已發表的研究數據進行比較，fexofenadine於台灣人的AUC與美國、德國、印度的受試者相似，但在某些亞洲人族群，包括韓國和日本族群，具有顯著不同。於基因研究也發現相似的現象。有機陰離子轉運體(OATP1A2)的多型性具有種族上的差異，且為運輸fexofenadine吸收進入細胞內的主要轉運體。依據研究結果推論fexofenadine的藥物動力學具有的遺傳變異與在OATP1A2活性差異相關。
並列摘要
The aim of the study was to consider the drug structure features and to develop sensitive LC-MS/MS methods for determination concentrations of metolazone and fexofenadine in human plasma. Development and validation of bioanalytical methods is important to understand the pharmacokinetics of drugs. LC-MS/MS is commonly used in laboratories for the qualitative and quantitative analysis of drug substances in drug products and in biological samples. In this work, two compounds that incorporate multiple-functional group moieties were investigated. Consider the functional groups of the drug structure and develop bioanalysis methods utilizing LC-MS/MS. The LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. The calibration curves found to be linear in the range 0.02 – 15 ng/mL for metolazone. The intra- and inter-day accuracy and precision coefficient of variation values were less than 6.3% at metolazone concentrations examined. The LOQ was found to be 0.02 ng/mL. The intra- and inter-day accuracy and precision coefficient of variation values were less than 6.7% (15.4% at LLOQ) at fexofenadine concentrations examined. The LOQ was found to be 1 ng/mL for each agent and the assay was found to generate a linear response up to 1000 ng/mL. Successful determination of metolazone or fexofenadine levels in circulating blood levels of health volunteers administered drugs orally. This work was aimed at obtaining pharmacokinetic data for metolazone and fexofenadine in Taiwanese following oral administration. Post normal distribution analysis, there was no evidence for a polymorphism in pharmacokinetics of metolazone in healthy male Taiwanese subjects. After analyzing fexofenadine pharmacokinetic parameters from healthy male Taiwanese subjects, the frequency distributions of AUC were shown to be tri-modal and to represent three pharmacokinetic phenotypes. Three groups were categorized as high absorption/exposure group, immediate absorption/exposure group and poor absorption/exposure group and mean AUCinf was 7376 ± 1006, 4731 ± 563 and 2816 ± 568 h×ng/mL, respectively. Taiwanese subjects may have different activity to uptake fexofenadine. In a comparison with published data, the mean AUCs of fexofenadine in the Taiwanese subjects were similar to that in American, German, and Indian subjects, but significantly different from that in some Asian populations, including Korean and Japanese ethnic groups. A similar phenomenon was observed in the generic studies. Organic anion transporting polypeptide 1A2 variation in human was shown ethnic difference and it was the major uptake transporter for fexofenadine absorption in the enterocyte. Results suggested that Taiwanese subjects showed genetic variation in fexofenadine pharmacokinetics that was associated with differences in organic anion transporting polypeptide 1A2 activity.