Pharmacokinetics of 3'-azido-3'-deoxythymidine and its catabolites and interactions with probenecid in rhesus monkeys
Pharmacokinetics of 3'-azido-3'-deoxythymidine and its catabolites and interactions with probenecid in rhesus monkeys
复制标题
DOI：
10.1128/aac.35.5.801
复制
发表时间：
1991-05
影响因子：
4.9
通讯作者：
E. M. Cretton;R. Schinazi;H. McClure;D. Anderson;J. Sommadossi
中科院分区：
文献类型：
--
作者：
E. M. Cretton;R. Schinazi;H. McClure;D. Anderson;J. Sommadossi
The pharmacokinetics and metabolism of 3'-azido-3'-deoxythymidine (AZT) were investigated in rhesus monkeys after subcutaneous administration of 33.3 mg of AZT per kg of body weight alone or in the presence of 100 mg of probenecid per kg. In addition to unchanged drug, two catabolites, 5'-O-glucuronide (GAZT) and 3'-amino-3'-deoxythymidine (AMT), were detected in plasma within 30 min. GAZT exhibited a kinetic profile similar to that of AZT, with an elimination half-life of approximately 1 h, while AMT was more variable, with an apparent half-life of 1.6 +/- 1.5 h. Approximately 90% of the total administered dose was recovered in urine within 24 h as AZT, GAZT, AMT, and the 5'-O-glucuronide of AMT. AZT and AMT demonstrated similar cerebrospinal fluid (CSF) penetration 1 h after AZT treatment, while GAZT poorly crossed the blood-brain barrier. Concomitant administration of probenecid greatly altered the pharmacokinetics of AZT, GAZT, and AMT, resulting in prolongation of their apparent elimination half-lives, increased concentrations in plasma, and marked reduction in renal clearances. In addition, the CSF/plasma concentration ratios for AZT and its catabolites were greatly increased, suggesting that probenecid inhibits efflux of AZT and its catabolites from CSF to plasma. The substantial levels of AMT in plasma suggest that this catabolite affects the pharmacodynamic properties of AZT in relation to its activity against human immunodeficiency virus replication and cytotoxicity to host cells. Enhanced AMT levels in plasma in the presence of probenecid may decrease the therapeutic efficacy of the AZT-probenecid combination.
