Mass spectrometric technique for the determination of N-phosphonoacetyl-L-aspartic acid in serum.
N-Phosphonoacetyl-L-aspartic acid (PALA), a potent inhibitor of aspartic acid transcarbamylase, is now undergoing Phase I clinical trials. Initial experiments revealed that PALA is not metabolized to phosphonoacetic acid (PAA) in humans. Thus PALA may be quantified in serum after in vitro conversion to PAA. Serum is deproteinized with perchloric acid, lipid extracted with methylene chloride, hydrolyzed with 8 N hydrochloric acid at 100 degrees for 3 h, and evaporated to dryness with nitrogen. The residue is silylated, and PAA is quantified by monitoring the (M + 1)+ ions of the protonated molecular ions of trimethylsilyl derivatives of PAA and phosphonopropionic acid (internal standard) obtained in chemical ionization with methane. Limit of detection is 0.5 microM (150 ng/ml) PALA using 1 ml serum. PALA was given by continuous infusion to cancer patients at various doses. Maximum levels of PALA (50-500 microM range) were obtained at the end of infusion, followed in most cases by biexponential decay. Persistent residual PALA levels (5 microM for 48 h after infusion) correlated with increased toxicity.
D000970:Antineoplastic Agents / Q000097:blood*; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006868:Hydrolysis; D013058:Mass Spectrometry; D009943:Organophosphorus Compounds / Q000097:blood*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000032:analysis / Q000097:blood*
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid