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研究生(外文):Shiou-I Lin
論文名稱(外文):Pharmacokinetics of nifedipine in Taiwan residents
指導教授:許光陽許光陽引用關係簡淑真Pharm. D.
指導教授(外文):Kuang-Yang Hsu, Ph. D.Sue-Chen Chien Pharm. D.
外文關鍵詞:nifedipinepharmacokineticsethnic diferrencesTaiwan
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Nifedipine (1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethyl ester, NF)為dihydropyridine類鈣離子通道阻斷劑,藥理作用為擴張心肌、冠狀動脈及週邊血管平滑肌,臨床上廣泛應用於高血壓、心絞痛、以及週邊血管疾病如Raynoud’s Phenomenon。NF的藥物動態學特性曾被廣泛的研究與討論,其中Ahsan、Renwick等人的研究結果發現,不同族群間NF之藥品動態具有顯著之差異。但有關於臺灣族群之NF藥品動態學研究則尚未見,由於NF的廣泛用途,也基於臺灣族群人民之福祉,因而衍生了本研究之進行。
本研究採用於台灣進行之藥品生體相等性試驗的數據,集合199位健康男性自願受試者,單次口服投與德國Bayer藥廠生產之NF (Adalat®)10 mg後,根據24小時內藥物血中濃度變化情形,運用non-compartment pharmacokinetics方法以及利用WinNonlin套裝軟體計算NF之藥物動態學參數,Cmax、Tmax、AUC及T1/2,並比較台灣居民與其他族群間之藥動學差異。以Student’s t test進行統計學上之雙尾檢定,訂定p<0.05為具有統計學上之意義。
本研究中,NF於台灣健康男性自願受試者吸收十分迅速,平均Cmax為143.24±53.37 ng/ml,Tmax中位數為0.50 (Q1,0.33~Q3,0.67)小時,平均AUC為297.12±124.62 ng ml-1 h,平均T1/2為3.3±1.8小時。其中不論是AUC、Cmax、T1/2皆比白種人高,且具有統計學上之意義 (p<0.001)。台灣人NF的 AUC及Cmax與日本人相似,顯示國人日本人具有相似的藥物動態學特性。而與白種人比較起來,NF於台灣族群之藥動學在AUC方面與白種人有顯著不同,顯示台灣族群對於NF之代謝有比白種人低的可能性。

Nifedipine (1,4-Dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5- pyridine dicarboxylic acid dimethyl ester, NF) is a dihydropyridine calcium channel blocker. NF has been shown to be an effective and relative well-tolerated treatment for stable, variant and unstable angina, mild to severe hypertension and Raynoud’s phenomenon.
Studies on NF pharmacokinetics have been published. It is well known that after oral administration there is great interindividual variability in disposition of NF. According to the published literature of NF, Ahsan and Renwick have found the ethnic differences among several populations.
The ethnic differences of NF metabolism have been reported in many studies,however the pharmacokinetics of NF in Taiwan residents has not been studied.
We conduted a retrospective review of NF bioequivalence studies which completed in the past five years in Taiwan. One hundred and ninty-nine healthy male volunteers who attend the bioequivalence studies were all within the range of ideal body weight. After an overnight fasting, each subject was given a single capsule containing 10 mg of Adalat® manufactured by Bayer, German, as a reference drug. Pharmacokinetic parameters (Cmax, Tmax, AUC and T1/2) which derived from Adalat® administered were calculated by non-compartmental analysis with WinNonlin® program. The difference of pharmacokinetic between Taiwan residents and other population were evaluated as well.
After administration of Adalat®, NF is absorbed very fast, the average Cmax of NF in healthy volunteers in Taiwan residents is 143.2±53.4 ng/ml, AUC is 297.1±124.6 ngml-1h and T1/2 is 3.3±1.8 hr, median of Tmax is 0.5 hr (Q1, 0.33~ Q3, 0.67). Compared to the published literature of NF in other population, the AUC, Cmax, and T1/2 of NF were significantly (p<0.001) higher in Taiwan residents than in Caucasians, however, the AUC and Cmax were similar between Taiwan residents and Japanese. According to the published antimode of AUC distribution, 22.5 ng«h/ml/mg, which proposed by Kleinbloesem, there are 69.3% subjects belong to slow metabolizer in Taiwan residents.
From the result above, there may be slower metabolism of NF in Taiwan residents than in Caucasians.

第一章 緒論1
第一節 藥物與族群差異3
(一) 族群間差異 (Ethnic differences)3
(二) 族群差異對藥物表現的影響因素 (Ethnic factors)4
(三) Nifedipine族群間藥動學差異6
第二節 化學特性及藥品安定性 10
第三節 臨床藥理學13
(一) 作用機轉13
(二) 臨床效果18
(三) 臨床用途19
(四) 使用劑量21
(五) 副作用及不良反應22
(六) 藥物交互作用22
(七) 禁忌症26
(八) 注意事項:26
第四節 藥物動態學27
(一) 吸收 (Absorption)30
(二) 分佈 (Distribution)32
(三) 代謝 (Metabolism)33
(四) 排除 (Elimination)37
(五) 年齡對nifedipine藥動學的影響38
(六) 疾病對nifedipine藥動學的影響39
第五節 研究目的41
第二章 研究方法42
第一節 研究對象42
第二節 資料統整42
第三節 數據分析43
(一) 電腦設備43
(二) 藥物動態學參數之計算43
(三) Nifedipine在台灣居民與其他族群之藥動學差異比較45
(四) 統計方法45
第三章 研究結果46
第一節 Nifedipine藥物動態學46
第二節 Nifedipine在台灣健康成年人與其他族群之藥動學差異比較 54
第四章 研究討論61
第一節 研究限制61
(一) NF藥物動態學參數計算61
(二) 族群間藥物動態學差異比較61
第二節 台灣居民之Nifedipine藥物動態學62
第三節 台灣居民與其他族群之nifedipine藥物動態學差異比較65
第四節 未來展望72
第五章 結論73

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