臺灣博碩士論文加值系統

淫羊藿是傳統中國醫學用來治療男性性功能異常及早洩的中藥藥物之
一。Sildenafil 是一種磷酸雙脂脢抑制劑,在西方醫學中常用來治療男 性勃起功能異常。Dapoxetine 是一種選擇性的血清素再吸收抑制劑,用 來治療男性早洩。本研究可分為兩個子類別,一方面利用超高效液相層 析分析方法來評估淫羊藿萃取物在大鼠體內與 sildenafil 間之藥物動力 學及藥物交互作用,另一方面則利用高效液相層析質譜分析方法來評估 淫羊藿萃取物在大鼠體內與 dapoxetine 間之藥物動力學及藥物交互作 用。在第一個研究中,大鼠先口服淫羊藿萃取物3天(1/2 克/公斤/天), 待大鼠麻醉後,進行經靜脈 sildenafil 注射(10/30 毫克/公斤),取大 鼠血清進行分析。藥物動力學結果發現 sildenafil 的曲線下面積在接受 口服高劑量淫羊藿萃取物有明顯下降現象。在第二個研究中,大鼠先口 服淫羊藿萃取物3天(2 克/公斤/天),於第4天投予經靜脈或口服之 dapoxetine 藥物 (10 毫克/公斤),發現單獨投予 dapoxetine 其曲線下 面積為 81 ± 13 minμg/mL,而若給予淫羊藿萃取物口服3天後,其 dapoxetine 之曲線下面積為 114 ± 13 minμg/mL 。淫羊藿萃取物與 dapoxetine 間並未存在明顯之藥物交互作用關係。由此2個研究中可發 現,淫羊藿萃取物在不同藥物間之藥物交互作用呈現出多樣化的藥物動 力學表現。在臨床醫療中,若要使用淫羊藿萃取物進行治療時,應先徵 詢專業人員意見以避免可能發生之藥物交互作用。

Epimedium sagittatum (Sieb. et Zucc.) Maxim is one of the herbs used to treat erectile dysfunction and premature ejaculation in Traditional Chinese Medicine. Sildenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction in Western Medicine. Dapoxetine is a selective serotonin reuptake inhibitor used for the management of premature ejaculation in Western medicine. This study was divided into two subsets, aiming to evaluate the herbal-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil in rats by ultra-performance liquid chromatography and the herb–drug interaction of Epimedium sagittatum extract on the pharmacokinetics of dapoxetine in rats by using high-performance liquid chromatography-tandem mass spectrometry. In the first part, the rat plasma was sampled from each anesthetized rat after pretreatment with 3-days Epimedium sagittatum extract (1/2 g/kg/day) and intravenous injection with sildenafil (10/30 mg/kg). The pharmacokinetic data demonstrate that the area under the concentration-time curve (AUC) of sildenafil (10 mg/kg) was significantly decreased in groups that received a high dose of Epimedium sagittatum extract. In the second part, the rat plasma was pretreated for 3 days with Epimedium sagittatum extract (2g/kg/day) and dapoxetine on the fourth day (10 mg/kg) by oral or intravenous administration. The AUC of oral dapoxetine was 81 ± 13 minμg/mL compared with 114 ± 13 minμg/mL in those pretreated with Epimedium sagittatum extract for 3 consecutive days. The herb drug pharmacokinetic interaction was not significant between Epimedium sagittatum extract and dapoxetine. In conclusion, the study demonstrates the
v
diverse pharmacokinetic activity of Epimedium sagittatum while used with different medications. The use of Epimedium sagittatum extract should be advised so as to prevent possible herb drug interaction in clinical practice.

Contents------------------------------------------------------------------------ i Acknowledgments-------------------------------------------------------------- v Chinese Abstract--------------------------------------------------------------- vi English Abstract--------------------------------------------------------------- vii Table of Contents ------------------------------------------------------------- ix 1. Introduction-------------------------------------------------------------------1
1.1 Erectile function ------------------------------------------------------------- 1
1.2 Ejaculation-------------------------------------------------------------------1
1.3 Erectile dysfunction in western medicine ------------------------------------ 2
1.4 Erectile dysfunction in traditional Chinese medicine --------------------------4
1.5 Premature ejaculation in western medicine ---------------------------------- 5
1.6 Premature ejaculation in traditional Chinese medicine ------------------------ 7
1.7 Interplay between erectile dysfunction and premature ejaculation ------------ 8
1.8 Brief introduction of Epimedium sagittatum---------------------------------- 9
1.8.1 Anti-inflammatory effect -------------------------------------------------- 9
1.8.2 Anti-proliferative effect--------------------------------------------------- 10 1.8.3 Anti-angiogenesis effect ------------------------------------------------- 10 1.8.4 Neuroprotective effect --------------------------------------------------- 10 1.8.5 Restoration of erectile function-------------------------------------------- 11
1.9 Brief introduction of sildenafil----------------------------------------------- 11
1.10 Brief introduction of dapoxetine ------------------------------------------- 12 1.11 Pharmacokinetics---------------------------------------------------------- 12 1.11.1 Liberation --------------------------------------------------------------- 13 1.11.2 Drugs absorption and distribution --------------------------------------- 13 1.11.3 Drugs metabolism and excretion----------------------------------------- 14 1.11.4 Pharmacokinetic parameters-----------------=--------------------------- 14 1.12 Herb drug interaction ----------------------------------------------------- 15
1.13 Transition phenomenon between traditional Chinese medicine
and western medicine--------------------------------------------------------- 16
2. Study motives and aim of study ----------------------------------------------18 3. Materials and Methods-------------------------------------------------------21
3.1 Chemicals and reagents ---------------------------------------------------- 21
3.2 Preparation of Epimedium sagittatum (Sieb. et Zucc.) Maxim extract --------21
3.3 Preparation of dapoxetine --------------------------------------------------22
3.4 Liquid chromatography ---------------------------------------------------- 22
3.5 High-performance liquid chromatography-tandem mass spectrometry------23
3.6 Plasma preparation of sildenafil extraction --------------------------------- 24
3.7 Preparation of dapoxetine extraction--------------------------------------- 24
3.8 matrix effect and extraction recovery -------------------------------------- 25
3.9 Accuracy and precision evaluation ----------------------------------------- 26 3.10 Stability evaluation ------------------------------------------------------- 26 3.11 Study protocol of herb drug interaction between Epicedium sagittatum and
sildenafil ------------------------------------------------------------------ 27
3.12 Study protocol of herb drug interaction between Epicedium sagittatum and
dapoxetine --------------------------------------------------------------- 28
3.13 Surgical procedures -------------------------------------------------------29
3.14 Data analysis------------------------------------------------------------- 30
4. Results ----------------------------------------------------------------------31 4.1 Pharmacokinetics and herb drug interaction between Epimedium sagittatum
and sildenafil --------------------------------------------------------------- 31 4.1.1 Analytic method validation for sildenafil ----------------------------------- 31 4.1.2 Pharmacokinegics of sildenafil in low dose Epicedium sagittatum extract (1
g/kg/day, p.o.) ----------------------------------------------------------- 31 4.1.3 Pharmacokinegics of sildenafil in high dose Epimedium sagittatum extract (2
g/kg/day, p.o.) ---------------------------------------------------------- 32 4.1.4 Effect of Epimedium sagittatum extract on the pharmacokinetics of sildenafil
(10 mg/kg, i.v.) ----------------------------------------------------------- 33
4.1 Pharmacokinetics and herb drug interaction between Epimedium sagittatum
and dapoxetine ------------------------------------------------------------ 34 4.2.1 Analytic method validation for dapoxetine -------------------------------- 34 4.2.2 Matrix effect, extraction recovery and stability for dapoxetine-------------35 4.2.3 Pharmacokinetics of dapoxetine i.v. -------------------------------------- 36 4.2.4 Pharmacokinetics of dapoxetine p.o. ------------------------------------ 36
4.2.5 Oral bioavailability of dapoxetine----------------------------------------- 37
5. Discussion ----------------------------------------------------------------- 38
5.1 Pharmacokinetic consideration between Epimedium sagittatum and sildenafil----------------------------------------------------------------------------------38
5.2 Pharmacokinetic consideration between Epicedium sagittatum and dapoxetine ------------------------------------------------------------------------------- 40
5.3 Study limitations------------------------------------------------------------41
6. Conclusion------------------------------------------------------------------44 References --------------------------------------------------------------------45 Tables------------------------------------------------------------------------- 55 Figures ------------------------------------------------------------------------66 Appendices --------------------------------------------------------------------72

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