TY - JOUR
T1 - Preclinical toxicological study of phosphonoacetic acid
T2 - Determination in blood by selected ion monitoring
AU - Roboz, John
AU - Suzuki, Robert
AU - Bekesi, George
AU - Hunt, Ronald
PY - 1977/10
Y1 - 1977/10
N2 - Confirmed observations of the inhibition of oncogenic viruses by phosphonoacetic acid led to preclinical trials in animal model systems. Circulating phosphonoacetic acid was detected in the blood of mouse, rabbit and monkey after oral or subcutaneous administration of the drug. Phosphonoacetic acid is quantified in blood, after removing proteins and lipids, as the trimethylsilylated derivative, by monitoring the intensity of the protonated molecular ion and also that of phosphonopropionic acid (internal standard) using chemical ionization mass spectrometry combined with gas chromatography. The detection limit is 20 ng ml−1 when 0.2 ml serum is analyzed. A dosage of 230 mg kg−1 day−1 by continuous infusion is proposed for therapeutic trials in monkeys. This dose is well tolerated and results in slowly increasing blood levels of phosphonoacetic acid which reach a maximum of approximately 50 μg ml−1 in a four day infusion, and decrease to 2 μg ml−1 24 h after termination.
AB - Confirmed observations of the inhibition of oncogenic viruses by phosphonoacetic acid led to preclinical trials in animal model systems. Circulating phosphonoacetic acid was detected in the blood of mouse, rabbit and monkey after oral or subcutaneous administration of the drug. Phosphonoacetic acid is quantified in blood, after removing proteins and lipids, as the trimethylsilylated derivative, by monitoring the intensity of the protonated molecular ion and also that of phosphonopropionic acid (internal standard) using chemical ionization mass spectrometry combined with gas chromatography. The detection limit is 20 ng ml−1 when 0.2 ml serum is analyzed. A dosage of 230 mg kg−1 day−1 by continuous infusion is proposed for therapeutic trials in monkeys. This dose is well tolerated and results in slowly increasing blood levels of phosphonoacetic acid which reach a maximum of approximately 50 μg ml−1 in a four day infusion, and decrease to 2 μg ml−1 24 h after termination.
UR - http://www.scopus.com/inward/record.url?scp=0017541486&partnerID=8YFLogxK
U2 - 10.1002/bms.1200040504
DO - 10.1002/bms.1200040504
M3 - Article
C2 - 410465
AN - SCOPUS:0017541486
SN - 1052-9306
VL - 4
SP - 291
EP - 296
JO - Biological Mass Spectrometry
JF - Biological Mass Spectrometry
IS - 5
ER -