Effect of pleural effusion on high-dose methotrexate kinetics

The kinetics of methotrexate were followed in a patient given two 6-hr infusions of 400 mg/kg in the presence and absence of a pleural effusion. Although the decline in serum concentrations during the first 30 hr after the infusion was similar for the two treatment courses, the half-life beginning 30 hr after the infusion was 6.7 hr without the pleural effusion and 14.4 hr with the pleural effusion. Comparison of the intercompartment distribution rate constants indicated slower movement of the drug back into the central compartment from the peripheral compartment when a pleural effusion was present. Pleural fluid methotrexate concentrations were consistently higher than serum concentrations. These data indicate that the increased risk of toxicity following high-dose methotrexate in patients with pleural effusions is due to changes in methotrexate kinetics resulting in delayed excretion.