Clinical pharmacologic studies of L‐asparaginase

Studies were performed with L‐asparaginase in patients with metastatic cancer and leukemia. The enzyme in human plasma had a broad optimal pH range and was stable in plasma at 40° C. for at least 40 days and at −10° C. for more than 4 months. Frequent freezing and thawing had no effect on the enzyme activity. The activity was not affected in vitro by the addition of 2 × 10 −3 M L‐aspartic acid, NH 4 C1, or (NH 4 ) 2 SO 4 . The initial plasma level following a single intravenous infection was dose related. The enzyme decrease in the plasma was exponential with half‐times varying among patients from 8 to 30 hours. In 15 patients who received daily doses there was a cumulative increase in plasma enzyme levels, but the half‐time did not change and rapid immune clearance was not observed. Plasma half‐time was not affected by age, sex, diagnosis, extent of disease, plasma lactic dehydrogenase levels, or hepatic or renal function. The apparent volume of distribution of the enzyme was slightly greater than the plasma volume. In a patient with a thoracic duct fistula it was found that the enzyme entered the extravascular space slowly and attained a concentration of 20 per cent the plasma level. Only a trace of L‐asparaginase activity was present in the cerebrospinal fluid and urine of patients after treatment.