Tranexamic acid在腎衰竭大鼠之神經毒性及藥物動力學研究

The neurotoxicity and pharmacokinetic study of tranexamic acid in renal failure rat

廖怡茹(Yi-Ju Liao)

指導教授 ： 黃耀斌

共同指導教授 ： 黃尚志(Shang-Jyh Hwang)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2009年)

https://doi.org/10.6832/KMU.2009.00075

摘要

研究背景：Tranexamic acid (TXA) 屬於抑制纖維蛋白溶解的藥物(antifibrinolytic agent)，臨床上用於預防或治療出血情形，除此作用外，TXA因結構與γ-aminobutyric acid (GABA)類似，為GABA受體拮抗劑，亦具有致癲癇性。在正常投與時其耐受性良好，然而案例報告顯示，有接受透析之病人在投與TXA後出現癲癇症狀。TXA有90%經由腎臟原型排除，並會分布至腦脊髓液中約為血中濃度的十分之一，在腎衰竭病人有可能會因為TXA排除不易而導致血中及腦脊髓液中藥物蓄積，因而引發癲癇。
研究方法：實驗使用250±50克雄性Sprague-Dawley種系大白鼠，以雙側輸尿管結紮法造成腎衰竭模式，並以血中肌酸酐值做為評估腎功能指標。本研究分為兩部分，在施行雙側輸尿管結紮24小時後，分別投與100、300及500 mg/kg TXA，進行神經毒性觀察試驗及經時取血液檢品分析血中及腦脊髓液TXA濃度，檢品經(2-naphthoxy) acetyl chloride衍生後以高效液相層析儀分析。
結果與討論：在腎功能正常組的平均血液肌酸酐值維持正常(0.19±0.06 mg/dl)，而腎衰竭大鼠在施行雙側輸尿管結紮後24小時候血液肌酸酐濃度明顯升高(2.53±0.49 mg/dl)。所有正常組大鼠皆未出現神經毒性反應；在腎衰竭組別則在給予500 mg/kg TXA後皆出現神經毒性反應，在兩個小時開始發作並擴散成全身性的痙攣，隨著劑量的降低，在投與300 mg/kg TXA的腎衰竭大鼠則遲至4-5個小時開始。當投予300 mg/kg以及500 mg/kg TXA於腎衰竭大鼠，其血中濃度均高於腎功能正常大鼠。經由本實驗觀察，TXA造成的神經毒性反應之強度及起始時間與所投與的藥物濃度有關，其嚴重程度也和所測得的藥物血中以及腦脊髓液濃度相符合，投予較大劑量TXA的腎衰竭大鼠會有較高的藥物血中濃度，亦較容易發生神經毒性。

關鍵字

腎衰竭 ； 透析 ； 傳明酸 ； 神經毒性 ； 癲癇 ； 藥物動力學

並列摘要

Background: Tranexmic acid (TXA) is a widely used antifibrinolysis agent in a variety of hemorrhage condition and also cause convulsion by γ-aminobutyric acid antagonist effect. The seizures were reported after intrathecal administration of TXA accidentally and three case reports about seizure after administrating TXA intravenously or orally on patients with renal failure. The pharmacokinetics studies showed that 90% of TXA was eliminated by renal as origin form and the concentration in cerebral-spinal fluid (CSF) is about one-tenth of blood concentration. The TXA could accumulate in patient with renal failure and the amount in brain may be enough to induce seizure.
Method: Male Sprague-Dawley rat weighting 250±50 g was received bilateral ureter ligation (BUL). The serum creatinine level was measured as the major marker of renal function. In this study, neurotoxicity and TXA level in blood and CSF were performed after dosing 100, 300 and 500 mg/kg. The concentration of TXA in plasma and CSF was derivatized with (2-naphthoxy) acetyl chloride (NAC) then analyzed using high performance liquid chromatography with fluorimetric detector.
Result and Discussion: The mean serum creatinine levels remained normal in the control rat and increased significantly in the rat with BUL. After dosing, all the renal failure rat given 500 mg/kg TXA and four of the six renal failure rats given 300 mg/kg TXA showed neurotoxicity sign as myoclonic twitching with chin, and extend to the whole body. The concentration of TXA in plasma between control rats and renal failure rat given 300 mg/kg and 500 mg/kg were difference and showed positive correlation with dose. The potentiation and onset of neurotoxicity of TXA with acute renal failure were related to the dose and renal function. It also had correlation with TXA concentration in plasma and CSF. The rats had renal failure or given higher TXA dose were shown higher TXA concentration in plasma and CSF and had neurotoxicity sign.

並列關鍵字

renal failure ； dialysis ； tranexamic acid ； neurotoxicity ； seizure ； pharmacokinetic study

參考文獻

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