Gruber S A, Canafax D M, Erdmann G R, Cipolle R J, Burke B A, Rabatin J T, Hynes P E, Gould F H, Heil J E, Ascher N L
Department of Surgery, University of Minnesota, Minneapolis 55455.
Transplantation. 1989 Dec;48(6):928-35. doi: 10.1097/00007890-198912000-00007.
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 immunosuppression. 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 i.a. 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 immunosuppressive metabolite of azathioprine, were determined during a continuous 24-hr i.a. 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 i.v. bolus, and systemic drug concentrations were determined over a 4-hr period. Mean +/- SE total-body clearance and elimination half-life were 887 +/- 159 ml/min and 1.4 +/- 0.2 hr, respectively, in the i.v. bolus study, indicating that 6-MP is rapidly cleared from the systemic 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 i.v. infusion of the same dose. According to the principles governing the advantages of i.a. infusions, these data demonstrate that 6-MP can be infused intrarenally to produce both a 4-fold increase in drug concentration within the kidney and an 80% decrease in systemic drug delivery when compared to same-dose i.v. administration. The overall result is the presence of a 30-fold gradient between local and systemic drug concentrations during intrarenal 6-MP infusion. We conclude that i.a. infusion of an immunosuppressive agent is technically feasible with preservation of renal function, and that 6-MP can be delivered locally in a canine model with great pharmacokinetic and potential therapeutic advantage.
鉴于最近的技术进步，我们开发了一种犬肾同种异体移植模型，利用可植入的、可编程的输液泵和生物相容性导管来重新探索局部免疫抑制的概念。13只杂种犬接受了双侧肾切除术，并通过肾 - 髂动脉端端吻合和肾 - 髂静脉端侧吻合进行了一侧肾脏的自体移植。将一根导入髂动脉的输液导管近端通过皮下隧道连接到一个可编程泵。第二根采样导管的尖端置于髂静脉内，刚好位于静脉吻合口近端。在持续19至63天的动脉内输注肝素化盐水期间，除1只动物发生肾盂肾炎和髂动脉导管尖端穿孔外，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的病例。在另外7只自体移植犬中，在连续24小时动脉内输注（10mg/kg/24小时）期间，同时测定了髂静脉和全身（颈静脉）中硫唑嘌呤的主要免疫抑制代谢产物6 - 巯基嘌呤（6 - MP）的浓度。输注结束后，对同7只犬静脉推注10mg/kg的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±标准误的全身清除率和消除半衰期分别为887±159ml/min和1.4±0.2小时，表明6 - MP可迅速从体循环中清除。出乎意料的是，肾脏可清除局部输注的6 - MP的60 - 95%，使进入体循环的活性药物量减少至静脉输注相同剂量时的5 - 40%。根据动脉内输注优势的相关原理，这些数据表明，与相同剂量的静脉给药相比，6 - MP可通过肾内输注使肾脏内药物浓度增加4倍，全身药物递送量减少80%。总体结果是在肾内输注6 - MP期间，局部和全身药物浓度之间存在30倍的梯度。我们得出结论，动脉内输注免疫抑制剂在技术上是可行的，且可保留肾功能，并且在犬模型中，6 - MP可通过局部给药获得巨大的药代动力学和潜在治疗优势。
