馬兜鈴酸在家兔體內之藥物動力學與腎毒性研究

馬兜鈴酸(AA)是馬兜鈴科(Aristolochiaceae)植物的主成分，為馬兜鈴酸Ⅰ(AAⅠ)及馬兜鈴Ⅱ(AAⅡ)所構成的混合物，研究指出AA具有腎毒性及腫瘤毒性，但對於AA在藥物動力學方面的研究報告則是相當有限。本研究採用高效液相層析法(HPLC)作為分析動物血漿檢品中AAⅠ、AAⅡ含量測定的工具，且分析法之確效試驗結果均符合生物檢品分析準則。本研究分別以單次靜脈投予不同劑量的AANa (0.25, 0.5, 1.0, 2.0 mg/kg)至四組家兔體內進行藥物動力學研究(每組均使用6隻家兔)，由於偵測極限的關係所以投予0.25 mg/kg AANa所得到的結果是以一室模式作配適，其他劑量則均使用二室模式作配適；除了0.25mg/kg的劑量之外，在0.5、1.0、2.0 mg/kg的劑量範圍內得到AAⅠ與AAⅡ的藥物動力學參數無統計上差異(P>0.05)，AAⅠ清除率依序為349.27?112.92、236.99?48.92、228.47?31.04、226.99?19.42 mL/h/kg，AAⅡ清除率依序為224.20?34.01、199.58?41.93、156.76?30.30、185.42?29.81 mL/h/kg，其給藥劑量(Dose)與藥物血中濃度曲線下面積(AUC)呈線性關係(AAⅠ: Y= 4754.23X-188.20, r2=0.980, P<0.001; AAⅡ: Y= 5728.56X-21.57, r2=0.911, P<0.001)。另外使用六隻家兔，以多次靜脈注射不同劑量(0.5、1.0、2.0 mg/kg) 的AANa到此六隻家兔體內，在這組研究中的每隻家兔每次給藥至少相隔七日，藥物動力學參數在靜脈給予0.5~2.0 mg/kg 之AANa的範圍內會改變，AAⅠ的清除率依序為236.99?48.92、 198.37?55.09、102.10?22.39 mL/h/kg，AAⅡ的清除率依序為199.58?41.93、97.63?23.22、42.31?7.64 mL/h/kg；其給藥劑量與曲線下面積得非線性藥物動力學的特徵(AAⅠ:Y=13618.09X2-875.43X + 469.52, r2=0.908, P<0.001; AAⅡ: Y=26583.73X2 - 3779.03X + 489.38, r2=0.948, P<0.001 )。非線性藥物動力學結果可能與AAⅠ、AAⅡ所造成的腎損傷導致清除率改變有關。在口服投予的研究則口服給予1.0 mg/kg 之AANa至家兔體內，AA在胃酸中不安定，會受到胃酸的強酸性而降解導致血漿中AAⅠ與AAⅡ的含量低，吸收情形沒有規則性，且個體間差異大，生體可用率不好。家兔在投予AANa後的第一日及第八日進行犧牲取其腎臟進行組織型態學研究，單次靜脈投予AANa得到的組織檢查如下所述：投予0.25 mg/kg後的第一日腎的型態學並沒有顯著的改變，在0.5、1.0、2.0 mg/kg的劑量之下則是觀察到輕微的細胞浸潤、腎小管上皮細胞變性萎縮的情形；在第八日觀察0.25 mg/kg的劑量下的損傷則是輕微的浸潤及腎小管上皮細胞萎縮情形，在0.5、1.0、2.0 mg/kg的劑量下則是發現有中度至嚴重的細胞間質浸潤、上皮細胞變性萎縮、間質纖維化及透明圓柱的沉積。口服投予1.0 mg/kg之AANa後，也於第一日及第八日取其腎臟進行組織型態學研究，口服投藥後的第一日組織形態學並無顯著變化，但到了第八日則觀察到輕微的上皮細胞變性萎縮及間質纖維化。根據組織形態研究結果得知腎臟損傷的程度會隨單次投藥劑量的增加而增加，且AA所造成的腎損傷有不斷在惡化的情形，但在腎絲球方面則未見損傷。

關鍵字

馬兜鈴酸；藥物動力學；腎毒性

並列摘要

Aristolochic acid (AA) is the main component of Aristolochia plants. It is a mixture of aristolochic acid Ⅰ(AAⅠ) and aristolochic acid Ⅱ(AAⅡ). It has been proved by several researches that AA has nephrotoxicity and tumor toxicity. However, the pharmacokinetics of AA is still limited. A validated high performance liquid chromatography (HPLC) method was used to determine the plasma concentration of AAⅠ and AAⅡ. The HPLC method used was met the guidance of bioanalytical method validation. The pharmacokinetics of AAⅠ and AAⅡ was studied by respectively intravenous administration of four different doses(0.25, 0.5, 1.0, 2.0 mg/kg ) of aristolochic acid sodium salt (AANa) in four groups of rabbits (n=6 for each group). Because of detection limit, the results of AAⅠ and AAⅡ from 0.25 mg/kg AANa were fit with one compartment model. Others were fit with two compartment model. There was no significant difference (P>0.05) in pharmacokinetic (PK) parameters of AAⅠ and AAⅡ, except 0.25 mg/kg AANa-treated group. The system clearance of AAⅠ were 349.27?112.92, 236.99?48.92, 228.47?31.04, 226.99?19.42 mL/h/kg. Clearance for AAⅡ were 224.20?34.01, 199.58?41.93, 156.76?30.30, 185.42?29.81 mL/h/kg. The area under the curves(AUC) of AAⅠ and AAⅡ were calculated from zero to infinite. The AUCs of AAⅠ and AAⅡ were proportional to the dose administrated (AAⅠ: Y= 4754.23X-188.20, r2=0.980, P<0.001; AAⅡ: Y= 5728.56X-21.57, r2=0.911, P<0.001). It indicated that AAⅠ and AAⅡ might behave dose-independent pharmacokinetics between 0.25~2.0mg/kg of AANa IV injection. In another study, six rabbits were intravenous administered with different doses (0.5, 1.0, 2.0 mg/kg) of AANa. All animal of this study were treated with AANa with 7 days interval. The PK parameters of AAⅠ and AAⅡ were changed between 0.5 ~ 2.0 mg/kg of AANa IV injection. The clearance of AAⅠ were 236.99?48.92, 198.37?55.09, 102.10?22.39 mL/h/kg. The clearance of AAⅡ were 199.58?41.93, 97.63?23.22, 42.31?7.64 mL/h/kg. The AUCs of AAⅠ and AAⅡ were not proportional to the increasing doses. The relationship of non-linear pharmacokinetic properties between dose and AUC were obtained (AAⅠ: Y=13618.09X2 - 875.43X + 469.52, r2=0.908, P<0.001; AAⅡ: Y=26583.73X2 - 3779.03X + 489.38, r2 = 0.948, P< 0.001 ). The non-linear pharmacokinetics might due to renal lesions caused by AAⅠ and AAⅡ. After oral administration of AANa 1.0 mg/kg, the gastric acid would destroy AA Ⅰand AAⅡ. The amount of AAⅠ and AAⅡ detected in plasma were very low. And the absorption of AAⅠand AAⅡ was not regularity and in high variation. After treated with AANa, rabbits were sacrificed on day-1 and day-8 to obtain the kidney sections. The histological examination of intravenous administration of AANa was described as the following. On day-1, there was no significant alteration in renal morphology on 0.25 mg/kg AANa-treated group. Mild interstitial infiltration, epithelial cell degeneration and atrophy were observed on 0.5, 1.0, and 2.0 mg/kg AANa-treated group. On day-8, mild degeneration of epithelium and atrophy were observed on 0.25 mg/kg AANa-treated group. Moderate to severe renal lesions including, interstitial infiltration, degeneration and atrophy of epithelium, interstitial fibrosis and hyaline cylinders were found on 0.5, 1.0 and 2.0 mg/kg group. Kidney sections were also obtained on day-1 and day-8 after oral treated with 1.0 mg/kg AANa to rabbits. In oral study, there was no significant change in renal morphology on day-1. But mild degeneration and atrophy of epithelium and interstitial fibrosis were observed on day-8. According to the histological examination, the extent of renal lesions increased with doses increasing was elucidated. The renal lesions caused by AA were continued to deteriorate. However, lesions in glomerulus were not observed.

並列關鍵字

aristolochic acid ； pharmacokinetics ； nephrotoxicity

參考文獻

7. 行政院衛生署. 2003. 行政院衛生署公告. ed.

59. 行政院衛生署. 2000. 中華藥典. 第五板 ed.

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2. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL 1994. Identification of aristolochic acid in Chinese herbs Lancet 343:174.

3. Cosyns J-P 2002. When is "aristolochic acid nephropathy" more accurate than "Chinese herbs nephropathy"? Kidney Int 61:1178.

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馬兜鈴酸在家兔體內之藥物動力學與腎毒性研究

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