Methotrexate clearance and clinical toxicity in osteosarcoma following high-dose methotrexate therapy

Two patients with osteogenic sarcoma were treated with high-dose methotrexate (MTX) followed by leucovorin 'rescue'. Profiles of MTX clearance from plasma and erythrocytes were obtained. Clearance of the drug from plasma during the first 36 hours appears to be biphasic with the first phase of elimination of the drug being appreciably more rapid than the second phase. The drug had also incorporated into the bone marrow precursor cells and reappeared after a few days in the circulating mature erythrocytes which may later serve as a slow-changing compartment for MTX. Nonspecific binding of the drug to plasma proteins may have been one of the causes of delayed clearance of plasma MTX observed in one of the patients. However, delayed clearance does not appear to correlate with the severity of clinical toxicity which was found to be more pronounced in a patient with a better clearance of the drug. Our results support the more recent concept that enhanced clinical toxicity may not be predictable by monitoring plasma MTX alone.