Carboxypeptidase G sub(2) rescue in patients with methotrexate intoxication and renal failure

The methotrexate (MTX) rescue agent carboxypeptidase G sub(2) (CPDG sub(2)) rapidly hydrolyses MTX to the inactive metabolite DAMPA (4-[[2,4-diamino-6-(pteridinyl)methyl]-methylamino]-benzoic acid) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is thought to be an inactive metabolite of MTX because it is not an effective inhibitor of the MTX target enzyme dihydrofolate reductase. DAMPA is eliminated more rapidly than MTX in these patients, which suggests a nonrenal route of elimination. In a phase II study (May 1997-March 2002), CPDG sub(2) was administered intravenously to 82 patients at a median dose of 50 U kg super(-1) (range 33-60 U kg super(-1)). Eligible patients for this study had serum MTX concentrations of >10 mu m at 36 h or >5 mu m at 42 h after start of MTX infusion and documented renal failure (serum creatinine greater than or equal to 1.5 times the upper limit of normal). Immediately before CPDG sub(2) administration, a median MTX serum level of 11.93 mu m (range 0.52-901 mu m) was documented. Carboxypeptidase G sub(2) was given at a median of 52 h (range 25-178 h) following the start of an MTX infusion of 1-12 gm super(-2) 4-36 h super(-1) and resulted in a rapid 97% (range 73-99%) reduction of the MTX serum level. Toxicity related to CPDG sub(2) was not observed. Toxicity related to MTX was documented in about half the patients; four patients died despite CPDG sub(2) administration due to severe myelosuppression and septic complications. In conclusion, administration of CPDG sub(2) is a well-tolerated, safe and a very effective way of MTX elimination in delayed excretion due to renal failure.