Roboz J, Suzuki R, Bekesi G, Hunt R
Biomed Mass Spectrom. 1977 Oct;4(5):291-6. doi: 10.1002/bms.1200040504.
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 microgram ml-1 in a four day infusion, and decrease to 2 microgram ml-1 24 h after termination.
对膦甲酸钠抑制致癌病毒的确认观察结果促使其在动物模型系统中进行临床前试验。在经口或皮下给药后，在小鼠、兔子和猴子的血液中检测到了循环的膦甲酸钠。在去除蛋白质和脂质后，通过使用化学电离质谱联用气相色谱法监测质子化分子离子以及膦丙二酸（内标）的强度，将血液中的膦甲酸钠定量为三甲基硅烷基化衍生物。当分析0.2 ml血清时，检测限为20 ng ml-1。建议在猴子的治疗试验中通过连续输注给予230 mg kg-1天-1的剂量。该剂量耐受性良好，导致膦甲酸钠的血药浓度缓慢升高，在四天的输注过程中最高可达约50微克ml-1，并在输注结束后24小时降至2微克ml-1。
