臺灣博碩士論文加值系統

沙利竇邁複雜的藥理活性，使它再度吸引生物醫學界研究的興趣，且其臨床的應用已延伸至許多過去難以治療的腫瘤及免疫方面疾病。然而，環顧過去有關其藥物動力(藥動)學之研究，可能因水溶性不佳而仍限於口服藥動學的研究，至於其游離態之藥動學則尚無相關報導。因此，本論文使用微透析採樣技術配合高效液相層析儀與紫外光偵測器組成的分析系統，針對靜脈注射沙利竇邁（1、3與10 mg/kg）後，大白鼠血液、腦部及膽汁中游離態沙利竇邁的藥動學進行研究。結果顯示，沙利竇邁在腦及膽汁中濃度皆在20分鐘內達最高，顯示其於腦血及膽血間快速達到平衡。比較所有劑量下之藥物濃度對時間曲線，發現在三部位互比時均呈現接近平行趨勢，顯示其於此三部位的濃度對時間變化的比率一定。沙利竇邁在血、腦及膽的t1/2及MRT均類似，顯示其排除時間在三部位無差異。血液藥動學的AUC與劑量呈現等比的成長，顯示在1-10 mg/kg的劑量下為線性藥動學。腦部與膽汁的AUC與劑量亦呈現等比的增加。游離態藥物分佈至腦部的比例（腦血分佈係數，AUCbrain / AUCblood）為0.82-0.86，而膽血分佈係數（AUCbile /AUCblood）為1.13-1.60，兩部位在劑量間均無差異性。
環孢靈素普遍用於對抗器官移植後的排斥現象與許多免疫疾病，臨床上環孢靈素合併沙利竇邁亦有效治療相關疾病，如心臟移植抗排斥及Behcet''s disease。然而對於環孢靈素是否在合併使用後可能改變沙利竇邁藥動學尚未有報告發表。因此本論文又以10 mg/kg環孢靈素合併3與10 mg/kg沙利竇邁進行交互作用的研究。結果顯示，於環孢靈素處理下，血中沙利竇邁仍呈線性藥動學；對10 mg/kg沙利竇邁，除沙利竇邁於血液中之MRT、t1/2及膽汁中的MRT略有延長外，其他藥動參數均無差異。對於3 mg/kg沙利竇邁，則腦部的AUC、Cmax略為增加，且膽汁中t1/2及MRT略為延長。此外，於環孢靈素處理下，沙利竇邁(3 mg/kg及10 mg/kg)之腦血及膽血分佈係數亦無明顯改變。由以上結果顯示環孢靈素對沙利竇邁藥動學之影響不顯著，又因環孢靈素為一P-醣蛋白抑制劑，此暗示P-醣蛋白對沙利竇邁的藥物動力學可能不扮演重要角色。

The complex pharmacological activities of thalidomide have again attracted lots of research interests in the biomedical field, and its clinical application has extended to numbers of carcinoma or immune disorders which were hard to cure before. However, previous relevant reports for the pharmacokinetic studies of thalidomide were restricted in the studies on oral route due to its poor water solubility, and there is no report on pharmacokinetic study on its unbound form. Therefore, in the present study, microdialysis sampling technique coupled with HPLC-UV was used to study the pharmacokinetics of unbound thalidomide in the blood, brain and bile after intravenous administration of thalidomide (1, 3 and 10 mg/kg) to Sprague Dawley rats. The results showed the Cmax in brain and bile was reached before 20 min, indicating fast concentration equilibrium of thalidomide in brain and bile with systemic circulation. Among all test doses, the concentration-time curves of blood, brain and bile were almost parallel to each other, indicating that the extents of concentration change with time in all sampling sites were similar. MRT and t1/2 in blood were statistically not different to those of brain and bile, suggesting elimination time in all sampling sites were unity. The blood AUC was proportional to the doses, suggesting a linear pharmacokinetics of unbound thalidomide. The extent of systemic unbound thalidomide distributed to brain and bile, defined as AUCbrain/AUCblood and AUCbile/AUCblood were 0.82-0.86 and 1.13-1.60, respectively. Furthermore, all these distribution ratios in each site were the same among different doses.
Cyclosporine has been used extensively as an immunosuppressive agent for transplant rejection and immune diseases. Cyclosporine combined with thalidomide has effectively treated some disorders, such as heart transplant rejection and Behcet''s disease. However, no study has reported whether cyclosporine can alter the pharmacokinetics of thalidomide in such combined use or not. Therefore, the interaction of cyclosporine (10 mg/kg) with thalidomide (3 and 10 mg/kg) was studied. In cyclosporine treated group, the blood pharmacokinetics of thalidomide still was linear. All pharmacokinetic parameters for 10 mg/kg thalidomide were not significantly changed except that blood MRT, t1/2 and bile MRT were slightly prolonged. For 3 mg/kg thalidomide, only slight increases in brain AUC and Cmax or bile t1/2 and MRT were observed. In addition, the AUCbrain/AUCblood and AUCbile/AUCblood for thalidomide (3 and 10 mg/kg) were not significantly changed by cyclosporine. In summary, cyclosporine appeared to have no obvious effect on the pharmacokinetic of thalidomide. Since cyclosporine is a P-glycoprotein inhibitor, these data suggest that P-glycoprotein may play no important role in the pharmacokinetics of thalidomide.

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