Pharmacokinetic study of cholesteryl-phosphoryl zidovudine in rats / 国际药学研究杂志

ABSTRACT

Objective: To develop and validate methods for determination of cholesteryl-phosphoryl zidovudine(CPZ)and its metabolite zidovudine(AZT)in rat plasma and tissues,and use the methods to investigate the pharmacokinetics of CPZ in rats. Meth- ods An HPLC-UV method was applied for the determination of CPZ in biological samples. The biological samples were precipitated with acetonitrile at first,and then CPZ was separated on a Diamonsil C 18 column(200 mm×4.6 mm I.D.,5 μm)with a gradient elution system comprising 90% methanol and 10% isopropanol(containing 2 mmol/L cetyl trimethylammonium bromide,2% acetic acid and 0.1% ammonium hydroxide). The eluent was monitored at 266 nm by UV detector. The determination of AZT in biological samples was performed by LC-MS/MS after it was extracted from the biological samples by liquid-liquid extraction with methyl tertbutyl ether. Chro- matographic separation was performed on a Poroshell 120 EC-C 18 column(50 mm×2.1 mm I.D.,2.7 μm). Using the mobile phase con- sisted of 35% methanol and 65% water containing 0.2% acetic acid,the column was eluted by an isocratic elution with the flow rate of 0.3 ml/min. Detection of AZT and the internal standard(IS)acetaminophen was achieved by ESI MS/MS in the positive ion mode using m/z 268.2→m/z 127.0 and m/z 152.1→m/z 110.0 transitions,respectively. Results: The linear ranges for the quantitative determina- tion of CPZ and AZT were 5-400 μg/ml and 2-500 ng/ml,respectively,when 50 μl plasma was analyzed. The lower limit for the quan- tification of CPZ and AZT was 5 μg/ml and 2 ng/ml,respectively. The inter-and intra-day precision values were below 15%,and the accuracy(relative error)was within ± 13.8% in all quality control samples. CPZ was quickly metabolized in rats,while AZT was oppo-site. The half-life of AZT was about 8 h. The distribution of CPZ and AZT was more in the liver,spleen and lungs of rats,and less in the heart and kidney. Conclusion: The methods completely meet the requirements for pharmacokinetic study of CPZ in rats. The phar- macokinetic results show that CPZ could release AZT targeting liver,spleen,and lungs in rats.