PHARMACOKINETICS AND PHARMACODYNAMICS OF 15-DEOXYSPERGUALIN IN A CANINE RENAL-ALLOGRAFT MODEL OF LOCAL IMMUNOSUPPRESSION

Local immunosuppression is based on the rationale that one can simulta neously prevent rejection and reduce systemic side effects by administ ering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/ catheter system to estimate the first- pass extraction of 15-deoxyspergualin (DSG) during renal artery infusi on and to compare the efficacy and toxicity of colatinuous intraarteri al (ia) versus intravenous (Iv) DSG delivery. Six autotransplanted dog s were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg /d). DSG was administered to allograft recipients by continuous ia inf usion at 0.5 (n = 11) and 0.75 (n = 8) mg/kg/day and by continuous iv infusion at 0.5 (n = 12) and 0.75 (n = 6) mg/kg/day. Mean +/- SD elimi nation half-life was 0.6 +/- 0.1 hr, and the transplanted kidney remov ed as much as 55-88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0.5 mg/kg/day) DSG produced a significant antirejection effect when g iven ia (MST = 12 days; P = 0.04) but not iv (MST = 9 days; P = 0.09), with equivalent overall mean drug levels during normal renal function . However, two of the four longest-surviving animals in the ia group d ied from severe systemic toxicity, manifested by anorexia, diarrhea, l eukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly pr olonged survival via both local (MST = 12 days; P = 0.04) and systemic (MST = 11 days; P = 0.02) routes, but half of the iv treated dogs die d from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug leve ls in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependent ly affected the severity of tubulointerstitial rejection and graft ede ma, and was not nephrotoxic. Our autotransplant pharmacokinetic data o verestimated the allografted kidney's ability to extract DSG during lo cal infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival b enefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advanta ge. (C) 1997 Academic Press.