馬兜鈴酸腎病變於家兔體內對

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

中文摘要

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。 英文摘要

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.