馬兜鈴酸腎病變於家兔體內對Inulin和p-Aminohippuric Acid藥物動力學研究

Pharmacokinetic Studies of Inulin and p-Aminohippuric Acid in Rabbits with Aristolochic Acid Nephropathy

曾喬詩(Chiao-Shih Tseng)

指導教授 ： 許光陽

共同指導教授 ： 簡淑真

臺北醫學大學/藥學院/藥學研究所/碩士(2007年)

摘要

馬兜鈴酸腎病變在組織型態學的特徵為主要損傷於近端腎小管，然而腎絲球形態相對的無影響。由於目前仍不甚清楚馬兜鈴酸對於腎絲球過濾，腎小管主動分泌等功能之影響。因此本實驗將單次靜脈注射投予0.5mg/kg AA sodium salt (AANa)在紐西蘭雄性家兔體內，第八天後引起中度腎小管間質之損傷。將腎小管間質之損傷以Sato等學者發表tubulointerstitial histological scores (THIS)進行量化評估，則損傷程度和正常兔子相比有顯著差異(5.03±1.05 vs. 2.09±1.23; P<0.01)。在此條件下分別以靜脈注射20mg/kg p-aminohippuric acid (PAH)和inulin，藉由PAH和inulin藥物動力學變化來推估腎臟血漿流量(renal plasma flow，RPF)與腎絲球過濾速率(glomerular filtration rate，GFR)。血漿中PAH和inulin之濃度以HPLC定量。實驗結果顯示在給予AANa後，PAH分佈(P=0.016)與排除相(P=0.026)半衰期均增加，而清除率(P=0.010)及中央室排除速率常數(P<0.001)皆減少；且PAH的藥物血中濃度對時間曲線下面積(AUC：vs. interstitial filtrateion；P=0.006，vs. total histological score；P=0.047)及排除相半衰期(β-t1/2：vs. hyaline cylinders；P=0.017，vs. interstitial fibrosis P=0.020)與腎小管間質損傷程度有顯著相關性，推測可能中度之近端腎小管損傷影響PAH藥物動力學參數變化，使得PAH排除減少。然而inulin的清除率(P=0.014)與排除速率常數(P<0.001)雖然減少，但藥物動力學參數則和腎小管間質損傷無顯著性相關性，可能是因inulin 僅經由腎絲球過濾排除。給予AANa前後，腎臟血漿流量(22.36±4.01 vs. 10.11±2.72mL/kg/min)與腎絲球過濾速率(5.95±1.79 vs. 0.89±0.18mL/kg/min)均顯著性(P<0.05)減少。由於GFR(-82.84±2.81%)和RPF(-50.55±13.59%)以不等比之下降，推測可能是因入球動脈之血管收縮導致GFR改變較多。另外，也觀察到腎小管陰離子主動分泌(33.34 vs. 18.27mL/min)呈現下降之趨勢。因為腎絲球過濾及腎小管主動分泌有不同程度之影響，所以臨床上在考量患者之用藥劑量建議應需依據當時病患的GFR和腎小管主動分泌之功能而調整。本實驗顯示馬兜鈴酸腎病變雖然主要損傷在近端腎小管，但對於腎臟血漿流量與腎絲球過濾速率均是減少。

關鍵字

馬兜鈴酸 ； 腎絲球過濾速率 ； 腎毒性 ； 腎功能 ； 腎臟血漿流量

並列摘要

On morphology of AAN, the proximal tubules were the main target of AA-related nephrotoxicity. It is interesting to note that glomerular structure were not affected. This study was done to speculate renal function changes while AAN presented. This study was performed via a single i.v. administration of 0.5mg/kg AA sodium salt (AANa) for 8 days resulted in the appearance of moderate tubulointerstitial lesions in male New Zealand white rabbits. Taking the grading system to evaluate AA-induced tubulointerstitial lesions, the sum of the histological scores were increase by comparison with normal rabbits. (2.09±1.23 vs. 5.03±1.05; P<0.01). Then 20mg/kg of p-aminohippuric acid (PAH) and inulin was iv administered respectively. The renal plasma flow (RPF) and glomerular filtration rate (GFR) changes were assessed by changes of pharmacokinetics of PAH and inulin. The concentrations of PAH and inulin in plasma was determined by HPLC methods. RPF was calculated as CLPAH/EPAH and EPAH is the PAH excretion ratio. The results showed that effects of 0.5mg/kg AANa treatment on PAH in rabbits were α-t1/2 (P=0.016) and β-t1/2 (P=0.026) significantly increased and CL (P=0.010) and k10 (P<0.001) were significantly decreased. The pharmacokinetic parameters of PAH, AUC (vs. interstitial filtrateion；P=0.006，vs. total histological score；P=0.047) and β-half-life (vs. hyaline cylinders；P=0.017，vs. interstitial fibrosis；P=0.020), were significantly correlated with the levels of tubulointerstitial lesions. Changes in the pharmacokinetic data of PAH might have resulted from the moderate alterations observed in the proximal tubules. Although effects on inulin were CL (P=0.014) and k (P<0.001) significantly decreased, there was no significantly correlation between pharmacokinetic data and tubulointerstitial lesions. Inulin only eliminated via filtration could be a explanation. And RPF with AAN were decreased when compared with controls (22.36±4.01 vs. 10.11±2.72mL/kg/min; P<0.05). For GFR were also decreased (5.95±1.79 vs. 0.89±0.18mL/kg/min; P<0.05). The different proportional fall in GFR (-82.84±2.81%) and RPF (-50.55±13.59%) suggests preglomerular vasoconstriction led GFR changes so much. We also found that tubular anion secretion (33.34 vs. 18.27mL/min) tend to decline. Thus, consideration dosage adjustment in clinical practice not only based on GFR but also the ability of tubular secretion. This study demonstrates that the renal function RPF and GFR were decreased while AA-induced major injure in the proximal tubules.

並列關鍵字

Aristolochic acid ； GFR ； Nephrotoxicity ； Renal function ； RPF

參考文獻

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