The protein binding and elimination of methotrexate after intravenous infusions in cancer patients.

1. Total serum concentrations and protein binding of methotrexate (MTX) have been studied after fifty-eight 6 h MTX infusions in nineteen cancer patients. 2. There was a linear relationship between dose (mg/kg) and serum MTX concentration at termination of infusion. 3. The elimination of total serum and "free' MTX followed similar bi-exponential expressions during the 72 h studied after the infusion. 4. Of the eight occasions when total serum concentrations did not fall below 10(-7) mol/l on the third day, five were associated with toxicity. 5. Mean per cent MTX bound by sera from the nineteen patients was 47.2 (s.d. = 4.4) per cent and appeared to be independent of MTX concentration within the range studied. 6. This study suggests that the very high binding previously reported for MTX should be questioned and that measurement of total serum MTX concentration (bound plus free) is sufficient for the recognition of patients who might be at risk of developing toxicity.