Following administration of HDMTX, two metabolites, 7-hydroxy-methotrexate (7-OH-MTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA), are observed in plasma. Within 1224 hours of the start of a HDMTX infusion, the plasma concentration of 7-OH-MTX, formed by the action of the enzyme aldehyde oxidase, exceeds the concentration of MTX [21, 22]. Intracellular polyglutamation of 7-OH-MTX results in prolonged retention and enhanced cytotoxicity [23]. DAMPA, a minor, inactive [2426] metabolite of MTX, accounting for <5% of the total dose of drug that is excreted in urine [24], is presumably formed from MTX that is excreted into the intestinal tract, hydrolyzed by bacterial carboxypeptidases, and then reabsorbed.

  PATHOGENESIS OF MTX-INDUCED RENAL DYSFUNCTION

  The etiology of MTX-induced renal dysfunction is believed to be mediated by the precipitation of MTX and its metabolites in the renal tubules [21, 22, 27] or via a direct toxic effect of MTX on the renal tubules [17]. More than 90% of MTX is cleared by the kidneys [13]. MTX is poorly soluble at acidic pH, and its metabolites, 7-OH-MTX and DAMPA, are six- to tenfold less soluble than MTX, respectively [21, 24]. An increase in the urine pH from 6.0 to 7.0 results in a five- to eightfold greater solubility of MTX and its metabolites, a finding that underlies the recommendation of i.v. hydration (2.53.5 liters of fluid per m2 per 24 hours, beginning 12 hours before MTX infusion and continuing for 2448 hours) and urine alkalinization (4050 mEq sodium bicarbonate per liter of i.v. fluid) prior to, during, and after the administration of HDMTX.

  Shorter durations of HDMTX infusions with resultant higher plasma and urinary MTX concentrations may carry an increased risk for renal dysfunction.

  Several drugs have been associated with increased toxicity when coadministered with MTX. The most significant interactions involve agents that interfere with MTX excretion, primarily by competing for renal tubular secretion, such as probenecid, salicylates, sulfisoxazole, penicillins, and nonsteroidal anti-inflammatory agents [2831].

  MTX-induced renal dysfunction results in sustained, elevated plasma MTX concentrations, which in turn may lead to ineffective rescue by LV and a marked enhancement of MTX’s other toxicities, especially myelosuppression, mucositis, hepatitis, and dermatitis [2, 3, 9, 14, 15].

  Vomiting and diarrhea during or shortly after the administration of MTX have been observed in patients who developed MTX toxicity [32, 33], but the majority of patients with renal dysfunction are initially asymptomatic, and most present with nonoliguric renal dysfunction [14, 32, 34]. An abrupt rise in serum creatinine during or shortly after MTX infusion indicates the development of renal dysfunction and can result in significantly elevated plasma MTX concentrations. Although the risk for MTX toxicity is dependent upon the dose and schedule of administration, plasma MTX concentrations should be 1.0 μM at 42 hours after the start of the HDMTX infusion, and plasma MTX concentrations 10 μM at this time point are associated with a high risk for the development of toxicities [2, 32, 33].

  In the absence of early diagnosis based on urine output, serum creatinine, and plasma MTX determination, coupled with intervention that includes pharmacokinetically guided increase in LV rescue, patients present following a delay of several days with severe mucositis, profound bone marrow suppression, and less commonly, dermatitis. Rescue attempts with even very high doses of LV at this symptomatic stage have a small likelihood of relieving MTX toxicities. Significantly elevated liver function tests have been associated with HDMTX administration but do not appear to be associated with the development of renal failure.

  INCIDENCE

  In the 1970s, prior to routine monitoring of plasma MTX concentrations and pharmacokinetically guided adjustment of LV, the mortality associated with HDTMX infusions ranged between 4.6% and 6% [3537]. Data from a number of studies performed in the 1970s found that elevated plasma MTX concentrations were predictive for the development of renal toxicities (Ta

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