Concentrations of N-(phosphonacetyl)-l-aspartate (PALA) in plasma and tears in man

Plasma concentrations of N - (phosphonacetyl) - l - aspartate (PALA) have been determined in 23 patients with advanced malignant disease during phase I/II clinical trial. Drug levels were determined by high pressure liquid chromatography. In 11 patients, who received PALA in a 1-hr infusion (doses ranging from 1 to 4 g/sq m), curves of plasma concentration vs time were constructed. The average absolute and relative total body clearances were 95 ± 24 ml/min and 1.43 ± 13 (± S.E.)ml/min, kg, respectively. Values of 27 ml/min and 0.52 ml/min, kg were measured in a patient with renal dysfunction. The apparent distribution volume was 0.29 l/kg, with an exception of 0.541 l/kg for a patient with a considerable amount of ascites fluid. The mean residence time was 3.2 ± 0.4 hr. Plasma peak levels and 24-hr concentrations of PALA were measured for 3-hr PALA infusion. Peak concentrations were lower and 24-hr concentrations were the same when compared with 1-hr infusion (4.9 × 10^-4 M compared to 9 × 10^-4 M and 2.3 × 10^-6 M compared to 2.45 × 10^-6 M, corrected for a dose of 2.5 g/sq m). In 7 patients PALA was measured in tears, due to the occasional occurrence of conjunctivitis during PALA treatment. A rapid increase in drug concentration to 10^-4 M-6 × 10^-4 M was measured within 2 hr from the start of 1-hr infusion in 7 patients with an average concentration ratio between plasma and tears of 3.7.