腎臟有機陰離子運輸蛋白之藥物交互作用於家兔體內藥物動力學研究

Pharmacokinetic Studies of Drug-Drug Interactions Involving Renal Organic Anion Transporter(OAT) in Rabbits

吳佳紋(Chia-Wen Wu)

指導教授 ： 許光陽

臺北醫學大學/藥學院/藥學系(碩博士班)/碩士(2013年)

摘要

近年來，越來越多研究顯示位於腎臟近端腎小管上皮細胞掌管物質進出的運輸蛋白(membrane transporters)可能與臨床上所產生之交互作用相關。位於腎臟近端腎小管的有機陰離子運輸蛋白(organic anion transporter,OAT)，其具有相當廣泛的受質專一性，當這些受質透過相同之運輸蛋白傳遞時，可能改變腎臟原有之排泄能力，而造成毒性累積或未達治療目標。本實驗為分別利用外源性以及內生性之OAT的受質probenecid以及肌酸酐(creatinine)，觀察在體外實驗中對於OAT具有高度親和力之diclofenac在家兔體內的藥物動力學，以探討生物體內與運輸蛋白OAT之間的交互作用。實驗以靜脈注射的方式分別投予單劑量probenecid(0.017moL;0.068moL)與單劑量diclofenac(0.017moL)至家兔體內(n=8)，觀察其個別之藥物動力學，再以靜脈給藥的方式合併投予單劑量probenecid與單劑量或多劑量之diclofenac，此外並同時觀察血漿creatinine濃度於投藥後的變化。動物實驗結果顯示，當以單劑量0.017moL diclofenac合併0.017moL、0.068moL probenecid後，diclofenac相較於單劑量單獨投予時其β-HL分別延長177.2±86.3%與414.9±267.8%、AUC0-inf 分別增加25.1±27.3%與63.6±30.7%、CL分別降低25.1±27.3%與63.6±30.7%，p<0.05。當以多劑量0.017moL diclofenac合併0.017moL probenecid後，diclofenac相較於單劑量單獨投予時其CL降低113.2±48.5%、β-HL延長238.0±82.7%、AUC0-inf增加113.1±48.5%，p<0.05；當以0.017moL、0.068moL probenecid合併單劑量0.017moL diclofenac時，probenecid相較於單獨投予時其AUC0-t分別提升49.1±40.5%與53.5±22.5%、β-HL分別延長173.0±222.9%與177.3±215.5%，p<0.05。當以0.068moL probenecid合併投予多劑量0.017moL diclofenac時，probenecid相較於單獨投予時其AUC0-t提升79.8±31.1%、CL降低79.4±35.2%、β-HL提升215.5±48.5%，p<0.05。投予0.068moL probenecid、單劑量0.017moL diclofenac，以及合併投予0.068moL probenecid與單劑量0.017moL diclofenac後，相較於未投予時，血漿creatinine濃度分別提升了8.69%、47.57%(p<0.01)，以及40.33%(p<0.05)。利用觀察外源性與內源性OAT受質於動物體內與diclofenac競爭的情形，顯示diclofenac在家兔體內OAT上產生競爭排泄而導致其藥物動力學上的改變，這樣的結果也與文獻中之細胞實驗有相同的情形。

關鍵字

有機陰離子運輸蛋白 ； 肌酸酐 ； 羧苯磺丙胺 ； 雙氯酚鈉

並列摘要

Recently, specific drug transporters located in epithelium of proximal tubules were considered be involving in drug interactions in numerous clinical researches. Furthermore, the purpose of the study was to investigate the renal transporter: organic anion transport(OAT) of the effect on the pharmacokinetics. The exogenous and endogenous OAT substrates probenecid and creatinine were used as index compounds in vivo to discuss with drug interactions between OAT and diclofenac, which with a high affinity to OAT in vitro. Diclofenac(0.017moL) and probenecid(0.017moL;0.068moL) were administered by I.V. bolus in each rabbits(n=8)respectively, then single-dose or multiple-dose diclofenac were combined with probenecid by I.V. bolus in each rabbits and endogenous creatinine concentration were observed simultaneously.In animal studies showed that when comparing to single-dose 0.017moL diclofenac alone, the parameters of diclofenac after single dose 0.017moL diclofenac combined with 0.017moL or 0.068moL probenecid that β-HL increased 177.2±86.3% and 414.9±267.8%, AUC0-inf increased 25.1±27.3% and 63.6±30.7%, CL decreased 25.1±27.3% and 63.6±30.7%, p<0.05. When comparing to single-dose 0.017moL diclofenac alone, the parameters of diclofenac after multiple-dose 0.017moL diclofenac combined with 0.017moL probenecid that β-HL increased 238.0±82.7%, AUC0-inf increased 113.1±48.5%,CL decreased 79.4±35.2%,p<0.05. By administering with 0.068moL probenecid, single-dose 0.017moL diclofenac, or both that plasma creatinine concentration were increased by 8.69%, 47.57%(p<0.01), and 40.33%(p<0.05) respectively. In the study, probenecid and creatinine were used as OAT substrates to discuss the OAT on pharmacokinetic in vivo. The data show that diclofenac by renal excretion might involving in OAT, which significantly change the pharmacokinetic parameters of diclofenac in the rabbits.

並列關鍵字

OAT ； creatinine ； probenecid ； diclofenac

參考文獻

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