Pharmacological disposition of N-(phosphonacetyl)-L-aspartate in humans

The pharmacological disposition of N-(phosphonacetyl)-L-aspartate (PALA), an antitumor transition state analog currently in clinical trial, has been studied in 19 patients after i.v. administration of the agent at doses ranging from 800 to 5000 mg/sq m; PALA in biological specimens was assayed enzymatically, advantage being taken of its inhibition of L-aspartate carbamoyltransferase (EC 2.1.3.2) PALA disappeared from plasma biexponentially, with an average terminal t 1/2 of 5.3 hr. It was excreted in the urine unchanged; the 24-hr cumulative excretion was 85% of the administered dose. The average total clearance was 1.60 ml/kg/min and was linearly related to creatinine clearance, suggesting that in humans PALA is essentially cleared by glomerular filtration. The apparent volume of distribution of PALA was 309 ml/kg, approximately the sulfate space in humans. PALA penetrated into the central nervous system only to a limited extent. Tumor L-aspartate carbamoyltransferase activity was also measured before and 1.5 hr to 6 days after PALA administration; in all eight studies, a notable decrease in enzyme activity was observed.