氣喘中藥材之研究 第二報 Geniposide對氣喘天竺鼠氣管穿透性的影響及其藥物動力學之探討

Studies on Asthmatic Chinese Medicine Ⅱ Effect of Geniposide on Tracheal Permeability of Guinea Pigs and Its Pharmacokinetics

趙彥欽(Yen-Chin Chao)

指導教授 ： 廖嘉鴻 ； 楊玲玲 ； 顏焜熒

臺北醫學大學/藥學院/生藥學研究所/碩士(1995年)

摘要

氣喘是一種呼吸道發炎性疾病，在初期發生時，會有呼吸道上皮穿透性增加、微血管通透性增加，導致末期氣管上皮組熾黏膜水腫、黏液栓塞形成、嗜酸性球浸潤等會封於呼吸道上皮細胞造成結構性的破壞，而使致敏原容易由細胞間隙通透而引發氣喘；如能將受損上皮細胞修復或使其穿透力降低，便能減少外來致敏原進入，緩和氣喘症狀。本實驗便以傳統中藥材中具有抗發炎、保肝、利膽等作用的中藥材─梔子中抗發炎活性主成份 geniposide，調製成噴霧劑裡，探討其對於以ovalbumin致敏的天竺鼠之氣管作離體適透性實驗。研究結果額示geniposide 10mM濃度時，能使已致敏之離體天竺鼠氣管組織穿透係數了由1.92±0.11x10(-5)cm/sec降低至與正常組1.49±0.16x10(-5)cm/sec接近，另以50mM geniposide濃度噴霧給藥方式時，更能對於急性氣喘之氣管組織具有保護及修復上皮細胞間隙結構之功效。 根據文獻報導，geniposide在酸性及熱中相當安定，在腸中則很容易受酵素分泌代謝，除此，其有關的藥物動力學研究報告很少，加上第一部份的研究已指出geniposide以噴霧給藥的方式能有效的降低氣喘天竺鼠氣管上皮通透性而緩和氣喘症狀，為了進一步發展臨床治療氣喘噴霧劑型的設計，第二部份的研究即針對geniposide於兔子體內的藥物動力學加以分析。分別以靜脈注射geniposide 2mg/kg、5mg/kg及10mg/kg的劑量，利用逆相管柱之高效液相層析法在移動相為H20-CH3CN-THF=90:8:2的條件下，以UV240nm測定geniposide在兔子血清中濃度的變化。結果發現geniposide於兔子體內約藥物動力學變化為二室體模式，平均分佈相的半衰期為2.945±0.25lmin，平均消失相的半衰期為16.305±1.435min，分佈體積為O.210±0.021 liter/kg，清除率為0.027±0.012 liter/min/kg，以能率(moment)模式計算時，其平均滯留體內時間為17.514±0.382min。

關鍵字

氣喘 ； 藥物動力學

並列摘要

Asthma is a common disease of airway inflammation, and smite one of the important pathological manifestation is increased airway epithelial permeability. Due to the penetration of the allergens from airway lumen through tracheal epithelia, it causes mucus plugging and eosinophil infiltration by release mediators of as well as the damage to airway epithelial tissue. Therefore decreasing epithelial permeability, it could improve asthmatic tissue injuries and reduce asthmatic symptoms. Geniposide, a major component from Gardenia jasminoides Ellis, has been used an antiphlogisic, a diurtic and a chalaogues in Chinese medicine. We have investigated the anti-inflammatory of geniposide effect on guinea pig trachea by introduction of inhaled ovalbumin challenge-induced. The data showed that 10mM of geniposide had protective effect on the asthmatic tracheal permeability. In addition, using aerosol dosage form of 50mM geniposide, it could improve the integrity of asthmatic tissues and preserve the tight junction structure. In order to understand the bioavailability of geniposide, we investigated the parameters of IV basic pharmacokinetics. A high- performance liquid chromatographic method used for the determination of geniposide in rabbit serum was developed. Geniposide in rabbit serum was extracted under methanoi denaturation condition and then injected into a reverse-phase column, it could be detected at UV 240nm using H20-CH3CN-THF=90 : 8 : 2 as the mobile phase. The results showed that the effect of geniposide could be fit into a two compartment model in vivo of rabbit and the average α (distribution-half life was 2.945±0.251 minutes, β (elimination-half life was 16.305 ±1.435 minutes, overall the central volumn of distribution(V1) was 0.210 ±0.021 liter/kg, and the clearance rate was 0.027±0.012 liter/min/kg. In the model model, the mean residence time was calculated to be 17.514 ±0.382 minutes.