The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model.
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.
Gruber
S A
SA
Department of Surgery, University of Minnesota, Minneapolis 55455.
Canafax
D M
DM
Erdmann
G R
GR
Cipolle
R J
RJ
Burke
B A
BA
Rabatin
J T
JT
Hynes
P E
PE
Gould
F H
FH
Heil
J E
JE
Ascher
N L
NL
D000818:Animals; D001379:Azathioprine / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D007260:Infusion Pumps; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012079:Renal Circulation; D014182:Transplantation, Autologous
D015122:Mercaptopurine; D001379:Azathioprine