The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model.
The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model.
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犬肾移植模型中局部 6-巯基嘌呤输注的药代动力学优势。
DOI：
10.1097/00007890-198912000-00007
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发表时间：
1989
期刊：
影响因子：
6.2
通讯作者：
Ascher,NL
中科院分区：
文献类型：
--
作者：
Gruber,SA;Canafax,DM;Erdmann,GR;Cipolle,RJ;Burke,BA;Rabatin,JT;Hynes,PE;Gould,FH;Heil,JE;Ascher,NL
根据最新的技术进展，我们开发了一种利用植入式可编程输液泵和生物相容性导管的犬肾移植模型，以重新探讨局部免疫抑制的概念。13只杂种犬行双侧肾切除术，1只经肾髂动脉端端吻合和肾髂静脉端侧吻合行自体肾移植。将导入髂动脉的输注导管的近端隧道连接至皮下放置的可程控泵。将第二根采样导管的头端置于髂静脉中，紧邻静脉吻合口。在19 - 63天的肝素化生理盐水静脉内输注期间，除1只动物发生肾盂肾炎和髂动脉导管头端穿孔外，所有动物的血清肌酐均保持正常。尸检时未观察到动脉血栓形成或导管移位。在另外7只自体移植犬中，在连续24小时IA输注（10 mg/kg/24 h）期间，同时测定了6-巯基嘌呤（6-MP）（硫唑嘌呤的主要免疫抑制代谢产物）的髂静脉和全身（颈静脉）浓度。输注结束后，对相同的7只犬静脉推注10 mg/kg 6-MP，并在4小时内测定全身药物浓度。在静脉推注研究中，平均值±SE全身清除率和消除半衰期分别为887±159 ml/min和1.4±0.2 hr，表明6-MP从体循环中快速清除。出乎意料的是，肾脏去除了多达60-95%的局部输注的6-MP，将进入体循环的活性药物的量减少到相同剂量静脉输注期间存在的量的5-40%。根据IA输注优势的原则，这些数据表明，6-MP可以通过肾内输注产生4倍的药物浓度增加，
In light of recent technologic advances, we developed a canine renal allograft model utilizing implantable, programmable infusion pumps and biocompatible catheters to reexplore the concept of local immunosuppres-sion. Thirteen mongrel dogs underwent bilateral nephrectomy and autotransplantation of 1 kidney via end-to-end renal-iliac artery and end-to-side renal-iliac vein anastomoses. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein just proximal to the venous anastomosis. During a period of ia infusion of heparinized saline ranging from 19 to 63 days, serum creatinine remained normal in all but 1 animal, which developed pyelonephritis and catheter-tip perforation of the iliac artery. No cases of arterial thrombosis or catheter migration were observed at necropsy. In 7 additional autotransplanted dogs, simultaneous iliac vein and systemic (jugular vein) concentrations of 6-mercaptopurine (6-MP), the major immuno-suppressive metabolite of azathioprine, were determined during a continuous 24-hr ia infusion (10 mg/kg/24 hr). Following termination of the infusion, 10 mg/kg 6-MP was administered to the same 7 dogs as an iv bolus, and systemic drug concentrations were deter mined over a 4-hr period. Mean±SE total-body clear ance and elimination half-life were 887±159 ml/min and 1.4±0.2 hr, respectively, in the iv bolus study, indicating that 6-MP is rapidly cleared from the sys temic circulation. Unexpectedly, the kidney removed as much as 60–95% of locally infused 6-MP, reducing the amount of active drug entering the systemic circulation to 5–40% of that which would be present during an iv infusion of the same dose. According to the principles governing the advantages of ia infusions, these data demonstrate that 6-MP can be infused intrarenally to produce both a 4-fold increase in drug concentration