Mizoribine pharmacokinetics and pharmacodynamics in a canine renal allograft model of local immunosuppression

Scott A. Gruber, Gary R. Erdmann, Barbara A. Burke, Adyr Moss, Larry Bowers, William J.M. Hrushesky, Robert J. Cipolle, Daniel M. Canafax, Arthur J. Matas

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/kg) and i.a. infusion (5.0 mg/kg/day). Mean ± SD elimination half-life was 3.02±0.81 hr, and the transplanted kidney removed as much as 47-59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), and finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST]=8 days) when administered either locally (MST=9 days) or sys-temically (MST=12 days). All dogs receiving 4.0 mg/kg/day MZB i.a. died from rejection, and a survival advantage was still not realized (MST=7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (M9T=14 days; JP&0.03) but not when directly compared with the i.a. group (P=0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P=0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST=14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST=14 days) died from severe debility, though survival in both groups was prolonged over control values (P=0.01 and P=0.06, respectively). Coadministration of a subtherapeutic dose of oral CsA (5 mg/kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST=23; P=0.01) but not i.v. (MST=11; P=1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P=0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized. However, combination of oral CsA with i.a., but not i.v., MZB infusion conferred a survival advantage with lower systemic MZB concentrations, suggesting mediation via a local immunosuppressive effect.

Original languageEnglish (US)
Pages (from-to)12-19
Number of pages8
JournalTransplantation
Volume53
Issue number1
DOIs
StatePublished - Jan 1992

ASJC Scopus subject areas

  • Transplantation

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