跳到主要內容

臺灣博碩士論文加值系統

(54.80.249.22) 您好!臺灣時間:2022/01/20 07:16
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林家安
研究生(外文):Chia An Lin
論文名稱:Metformin在老鼠體內之藥動學交互作用
論文名稱(外文):Pharmacokinetic Drug-Drug Interaction of Metformin in Rats
指導教授:周辰熹周辰熹引用關係
指導教授(外文):Chen-Hsi Chou
學位類別:碩士
校院名稱:國立成功大學
系所名稱:臨床藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:84
中文關鍵詞:藥動學交互作用
外文關鍵詞:MetforminPharmacokinetic
相關次數:
  • 被引用被引用:0
  • 點閱點閱:1024
  • 評分評分:
  • 下載下載:120
  • 收藏至我的研究室書目清單書目收藏:0
Metformin (以下稱為MET)為雙胍類的口服降血糖藥物。過去大家均認為MET在體內不會被代謝而以原形經腎排除,且MET在腎中的主動分泌會受到cimetidine抑制。由於MET結構中具有胺基於生理pH值(7.4)下主要呈帶正電的陽離子狀態,且cimetidine為OCT的典型受質,故MET對細胞的穿透性極可能受OCT的調控。
然而文獻曾指出約有21 % MET疑似被代謝,但其機轉不明,且至今無任何代謝產物由體內被分離及確認。最近Ruggiero-Lopez等人指出於體外生理條件下,高濃度MET和高濃度的內生性二羰基化合物縮合成線性縮合物,而此縮合物會再進一步脫水生成七員雜環triazepinone。而本實驗室首先在灌流MET的老鼠肝臟發現一個MET與體內內生性毒物(methylglyoxal)的線性縮合產物(M5)。
在本研究中主要探討於不同給藥方式(靜脈注射與靜脈輸注)將MET注入老鼠體內後MET與其所產生的代謝物M5之動力學;並評估MET的動態與其代謝物M5的生成是否會受不同性別老鼠之影響;另外觀察不同藥品與MET併用後對MET及其代謝物M5的影響。
結果顯示在靜脈輸注實驗中,輸注速率為0.06 mg/min所得到的MET血漿中穩定濃度為1.01 ± 0.14 mg/L接近其血中治療濃度且此時的代謝物的濃度為0.04 ± 0.1 mg/L;cimetidine顯著抑制了MET的全身清除率(p<0.05),與文獻上人體測試之結果相似。cimetidine也同時抑制了M5的生成;在性別差異的研究中,MET在公老鼠與母老鼠中其動態並沒有顯著差異,在代謝物生成方面母老鼠雖然生成較少但在統計學上是沒有意義的。而在靜脈注射的實驗中,在將MET與不同藥品同時注入老鼠體內後發現,p — aminohippuric acid、glyburide、quinidine和nifedipine皆顯著抑制了MET的清除率而methanol的影響並不顯著。p — aminohippuric acid、nifedipine與glyburide並沒有顯著抑制代謝物的生成,而quinidine與methanol卻有。此結果大部分呼應了文獻上所提出MET與這些藥品的交互作用,同時也提供了觀察代謝物M5動態的訊息。
由實驗結果所得到的結論是MET在老鼠體內確實能產生代謝物,而且代謝物的生成量在不同性別老鼠中有些許的差異;在交互作用方面,於生理條件下會形成陽離子態的藥品對MET的影響較顯著。由於MET引起乳酸中毒的機率與其在體內的蓄積有關,而其代謝物M5之生成與內生性毒性物質methylglyoxal有關。因此,這些藥物與MET併服時,若對MET與M5之動態有顯著影響時,均應適當地加以注意以避免MET的蓄積而使MET產生副作用與毒性的機會增大。

Metformin (MET) is an oral biguanide antihyperglycemic agent. Met dose not undergo hepatic metabolism. It is eliminated unchanged in urine and its renal tubular secretion can be inhibited by the typical substrate of organic cation transporter (OCT). As MET is positively charged under physiological pH 7.4, the transport of MET in the body may also be mediated by OCT.
It has been proposed that about 21% of MET may be metabolized following oral administration, however no metabolites have been idenditified yet. It was demonstrated recently that MET strongly reacts with dicarbonyl compounds, such as methylglyoxal, forming guanidine-dicarbonyl adducts under in vitro physiological conditions. In our previous studies using isolated perfused rat liver preparation, we found a metabolite of MET (M5), which was later identified as the linear adduct of MET and the endogenous methylglyoxal.
The objectives of this study were to evaluate the disposition kinetics of MET and M5 following intravenous infusion and bolus administration of MET in rats;to investigate the gender difference in kinetics of MET and M5 between male and female rats;and to explore the role of OCTs in the drug-drug interactions of MET and M5 in rats.
In this study we have characterized the plasma and RBC concentration-time profiles of MET and its metabolite M5 in rats. The results showed that there was no significance difference in disposition kinetics of M5 and MET between male and female rats. Both cimetidine and quinidine changed the disposition kinetics of MET and M5 significantly. p— Aminohippuric acid、glyburide and nifedipine inhibited the clearance of MET with no significant effects on the disposition of metabolite.
In conclusion, MET reacted with endogenous methylglyoxal to produce the adduct metabolite M5 in the body. The disposition of MET and M5 showed relatively no significantly gender difference in rats. Drugs which are positively charged, such as cimetidine and quinidine, can significantly affect the kinetics of MET and M5. Therefore, care should be taken to avoid the occurrence of serious side effects when these drugs are concomitant with MET.

中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖目錄 IX
表目錄 XII
縮寫表 XII
第壹章 緒論 1
第一節 Metformin 簡介 1
一. 物化和藥動性質 2
二. 作用機轉 3
三. 副作用 3
四. 交互作用與禁忌症 3
第二節 有機離子載體 4
一. 分類 5
二. 運送 6
三. 性別差異 7
第貳章 研究目的 15
第一節 靜脈輸注(IV infusion)試驗 16
一. 劑量依性實驗 16
二. 性別差異實驗 16
三. 藥物交互作用實驗 16
第二節 靜脈注射(IV bolus)試驗 17
一. 單一劑量注射實驗 17
二. 藥物交互作用實驗 17
第參章 實驗材料、儀器及方法 20
第一節 實驗材料 20
一. 實驗動物 20
二. 藥品與試劑 20
第二節 實驗儀器 21
一. 手術用具及器材 21
二. 高壓液相層析系統 (HPLC system). 22
三. 其他 22
第三節 實驗方法 23
一. 插管手術 23
二. 藥品配製 24
三. 實驗設計 25
四. 樣品處理 27
五. 數據分析 28
第肆章 實驗結果 30
第一節 靜脈輸注 (IV infusion) 實驗 30
一. 劑量依性試驗 30
二. 性別差異試驗 31
三. 藥物交互作用試驗 32
第二節 靜脈注射 (IV bolus) 實驗 33
一. 單一劑量靜脈注射 33
二. 藥物交互作用試驗 34
第伍章 討論 55
第一節 靜脈輸注 (IV infusion) 實驗 55
一. 劑量依性試驗 55
二. 性別差異試驗 56
三. 藥物交互作用試驗 56
第二節 靜脈注射 (IV bous) 實驗 59
一. 單一劑量靜脈注射 59
二. 藥物交互作用試驗 59
第六章 結論 67
參考文獻 68
圖1-1 Metformin與Dicarbonyl Compounds之反應流程假說 9
圖1-2 有機陰離子於近曲小管的運送模式 10
圖1-3 有機陽離子於近曲小管的運送模式 11
圖1-4 有機陽離子於肝臟的運送模式 12
圖2-1 MET與MG體外試驗之HPLC分析圖譜 18
圖2-2 MET(100 mg/L)灌流老鼠肝臟之HPLC分析圖譜 19
圖3-1 靜脈輸注與靜脈注射之校正曲線圖 29
圖4-1 靜脈輸注0.006 mg/min Metformin 血漿與紅血球之濃度經時變化圖 37
圖4-2 靜脈輸注0.02 mg/min Metformin 血漿與紅血球之濃度經時變化圖 38
圖4-3 靜脈輸注0.2 mg/min Metformin 血漿與紅血球之濃度經時變化圖 39
圖4-4 靜脈輸注female rat 0.006 mg/min Metformin 血漿與紅血球之濃度經時變化圖 40
圖4-5 靜脈輸注 0.02 mg/min Metformin 與 0.2 mg/min Cimetidine 之Metformin 血漿與紅血球之濃度經時變化圖 41
圖4-6 靜脈輸注 0.02 mg/min Metformin 與 0.04 mg/min Furosemide 之Metformin 血漿與紅血球之濃度經時變化圖………….42
圖4-7 靜脈輸注實驗血漿藥物比較圖 43
圖4-8 靜脈輸注實驗RBC藥物比較圖 44
圖4-9 靜脈注射50 mg/kg Metformin 血漿與紅血球之濃度經時變化圖 46
圖4-10 靜脈注射50 mg/kg Metformin 與 0.1 mL Methanol 之Metformin血漿與紅血球之濃度經時變化圖 47
圖4-11 靜脈注射50 mg/kg Metformin 與10 mg/kg p — Aminohippuric acid之Metformin血漿與紅血球之濃度經時變化圖 48
圖4-12 靜脈注射50 mg/kg Metformin 與0.3 mg/kg Glyburide之Metformin血漿與紅血球之濃度經時變化圖 49
圖4-13 靜脈注射50 mg/kg Metformin 與5 mg/kg Quinidine之Metformin血漿與紅血球之濃度經時變化圖 50
圖4-14 靜脈注射50 mg/kg Metformin 與2 mg/kg Nifedipine之Metformin血漿與紅血球之濃度經時變化圖 51
圖4-15 靜脈注射藥物交互作用實驗血漿藥物比較圖 53
圖4-16 靜脈注射藥物交互作用實驗RBC藥物比較圖 54
圖5-1 本試驗中所用各種化合物的結構式 66
表1-1 有機陰離子之分子特色…………………………… 13
表1-2 有機陽離子之分子特色 14
表4-1 靜脈輸注相關參數 45
表4-2 靜脈注射相關參數 52
表5-1 本試驗中所用各種抑制劑的物化性質 65

Ahsan, C.H., Renwick, A.G., Macklin, B., Challenor, V.F., Waller, D.G. and George, C.F., Ethnic differences in the pharmacokinetics of oral nifedipine, Br J Clin Pharmacol, 31 (1991) 399-403.
Bailey, C.J. and Turner, R.C., Metformin, N Engl J Med, 334 (1996) 574-9.
Berkhin, E.B. and Humphreys, M.H., Regulation of renal tubular secretion of organic compounds, Kidney Int, 59 (2001) 17-30.
Bowman, H.M. and Hook, J.B., Sex differences in organic ion transport by rat kidney, Proc Soc Exp Biol Med, 141 (1972) 258-62.
Brogden, R.N., Heel, R.C., Speight, T.M. and Avery, G.S., Cimetidine: a review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease, Drugs, 15 (1978) 93-131.
Busch, A.E., Quester, S., Ulzheimer, J.C., Waldegger, S., Gorboulev, V., Arndt, P., Lang, F. and Koepsell, H., Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1, J Biol Chem, 271 (1996) 32599-604.
Campbell, T.J. and Williams, K.M., Therapeutic drug monitoring: antiarrhythmic drugs, Br J Clin Pharmacol, 46 (1998) 307-19.
Davidson, M.B. and Peters, A.L., An overview of metformin in the treatment of type 2 diabetes mellitus, Am J Med, 102 (1997) 99-110.
Grundemann, D., Babin-Ebell, J., Martel, F., Ording, N., Schmidt, A. and Schomig, E., Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells, J Biol Chem, 272 (1997) 10408-13.
Grundemann, D., Gorboulev, V., Gambaryan, S., Veyhl, M. and Koepsell, H., Drug excretion mediated by a new prototype of polyspecific transporter, Nature, 372 (1994) 549-52.
Holstein, A., Nahrwold, D., Hinze, S. and Egberts, E.H., Contra-indications to metformin therapy are largely disregarded, Diabet Med, 16 (1999) 692-6.
Lalau, J.D. and Race, J.M., Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis', Diabetes Obes Metab, 3 (2001) 195-201.
Lee, J.M. and Peuler, J.D., Acute vasorelaxant effects of metformin and attenuation by stimulation of sympathetic agonist release, Life Sci, 64 (1999) L57-63.
Lupi, R., Del Guerra, S., Tellini, C., Giannarelli, R., Coppelli, A., Lorenzetti, M., Carmellini, M., Mosca, F., Navalesi, R. and Marchetti, P., The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose, Eur J Pharmacol, 364 (1999) 205-9.
McArthur, K.E., Raufman, J.P., Seaman, J.J., Ziemniak, J.A., Gardner, J.D. and Jensen, R.T., Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome, Gastroenterology, 93 (1987) 69-76.
Meijer, D.K., Mol, W.E., Muller, M. and Kurz, G., Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cations, J Pharmacokinet Biopharm, 18 (1990) 35-70.
Melchior, W.R. and Jaber, L.A., Metformin: an antihyperglycemic agent for treatment of type II diabetes, Ann Pharmacother, 30 (1996) 158-64.
Nakamura, H., Sano, H., Yamazaki, M. and Sugiyama, Y., Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: contribution of type I system, J Pharmacol Exp Ther, 269 (1994) 1220-7.
Pancorbo, S., Bubrick, M.P., Chin, T.W., Miller, K.W. and Onstad, G., Cimetidine dynamics after repeated intravenous injection, Clin Pharmacol Ther, 35 (1984) 50-4.
Pentikainen, P.J., Neuvonen, P.J. and Penttila, A., Pharmacokinetics of metformin after intravenous and oral administration to man, Eur J Clin Pharmacol, 16 (1979) 195-202.
Riddle, M., Combining sulfonylureas and other oral agents, Am J Med, 108 Suppl 6a (2000) 15S-22S.
Ronald Arky, M., Charles S. et al., PHYSICIANS'DESK REFERENCE, Vol. 53 edition, Medical Economics Company, Inc., Montvale, 1999.
Ruggiero-Lopez, D., Lecomte, M., Moinet, G., Patereau, G., Lagarde, M. and Wiernsperger, N., Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation, Biochem Pharmacol, 58 (1999) 1765-73.
Sambol, N.C., Chiang, J., O'Conner, M., Liu, C.Y., Lin, E.T., Goodman, A.M., Benet, L.Z. and Karam, J.H., Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus, J Clin Pharmacol, 36 (1996) 1012-21.
Schimmer B, P.K., Goodman and Gilman's the pharmacological basis of therapertics., Vol. 9thed, McGraw-Hill, New Yourk, 1996.
Schulz, M. and Schmoldt, A., [A compilation of therapeutic and toxic plasma drug concentrations], Anaesthesist, 43 (1994) 835-44.
Schwinghammer, T.L., Antal, E.J., Kubacka, R.T., Hackimer, M.E. and Johnston, J.M., Pharmacokinetics and pharmacodynamics of glyburide in young and elderly nondiabetic adults, Clin Pharm, 10 (1991) 532-8.
Sirtori, C.R., Franceschini, G., Galli-Kienle, M., Cighetti, G., Galli, G., Bondioli, A. and Conti, F., Disposition of metformin (N,N-dimethylbiguanide) in man, Clin Pharmacol Ther, 24 (1978) 683-93.
Somogyi, A., Stockley, C., Keal, J., Rolan, P. and Bochner, F., Reduction of metformin renal tubular secretion by cimetidine in man, Br J Clin Pharmacol, 23 (1987) 545-51.
Sulkin, T.V., Bosman, D. and Krentz, A.J., Contraindications to metformin therapy in patients with NIDDM, Diabetes Care, 20 (1997) 925-8.
Sweet, D.H., Wolff, N.A. and Pritchard, J.B., Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney, J Biol Chem, 272 (1997) 30088-95.
Tucker, G.T., Casey, C., Phillips, P.J., Connor, H., Ward, J.D. and Woods, H.F., Metformin kinetics in healthy subjects and in patients with diabetes mellitus, Br J Clin Pharmacol, 12 (1981) 235-46.
Urakami, Y., Nakamura, N., Takahashi, K., Okuda, M., Saito, H., Hashimoto, Y. and Inui, K., Gender differences in expression of organic cation transporter OCT2 in rat kidney, FEBS Lett, 461 (1999) 339-42.
Wilcock, C. and Bailey, C.J., Accumulation of metformin by tissues of the normal and diabetic mouse, Xenobiotica, 24 (1994) 49-57.
Wu, X., Prasad, P.D., Leibach, F.H. and Ganapathy, V., cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family, Biochem Biophys Res Commun, 246 (1998) 589-95.
Yabuuchi, H., Tamai, I., Nezu, J., Sakamoto, K., Oku, A., Shimane, M., Sai, Y. and Tsuji, A., Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations, J Pharmacol Exp Ther, 289 (1999) 768-73.
Youssef, A., Madkour, K., Cox, C. and Weiss, B., Comparative lethality of methanol, ethanol and mixtures in female rats, J Appl Toxicol, 12 (1992) 193-7.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top