Nicolas F, De Sousa G, Thomas P, Placidi M, Lorenzon G, Rahmani R
INSERM, Centre de Recherche Agronomique, Antibes, France.
Drug Metab Dispos. 1995 Mar;23(3):308-13.
3'-Azido-3'-deoxythymidine (AZT), the main antiretroviral drug used against Human Immunodeficiency Virus, was approved by the Food and Drug Administration in 1987 with only little knowledge concerning its metabolism. The aim of our study was to evaluate the interspecies variability of AZT metabolism in primary cultures of hepatocytes, freshly isolated from rats, dogs, monkeys, and humans. Cultures were exposed to 10 or 100 microM [3H]AZT. Extracellular and intracellular compartments were analyzed using a HPLC method. Intracellular and extracellular metabolic patterns were qualitatively similar, but very low amounts of AZT and metabolites were detected within hepatocytes. In all species, the 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT) was identified as the major metabolite of AZT. In addition to this glucuronide, two minor peaks were detected: one coeluting with 3'-amino-3'-deoxythymidine(AMT); and the other with a retention time corresponding, on the basis of the publications in this field, to 3'-amino-3'-deoxythymidine glucuronide. However, further investigation allowed this compound to be characterized as tritiated water, possibly representing a catabolic endproduct of AZT. Although glucuronidation was the main metabolic pathway in the four species studied, AZT biotransformation rate was much lower in rat and dog hepatocytes than in monkey and human ones. Finally, an excellent correlation was obtained between in vivo and in vitro metabolic data.
3'-叠氮-3'-脱氧胸苷（AZT）是用于对抗人类免疫缺陷病毒的主要抗逆转录病毒药物，于1987年获得美国食品药品监督管理局批准，当时对其代谢了解甚少。我们研究的目的是评估从大鼠、狗、猴子和人类新鲜分离的肝细胞原代培养物中AZT代谢的种间变异性。将培养物暴露于10或100微摩尔[3H]AZT。使用高效液相色谱法分析细胞外和细胞内部分。细胞内和细胞外代谢模式在质量上相似，但在肝细胞内检测到的AZT和代谢物量非常低。在所有物种中，3'-叠氮-3'-脱氧-5'-O-β-D-吡喃葡萄糖醛酸胸苷（GAZT）被鉴定为AZT的主要代谢物。除了这种葡糖醛酸苷外，还检测到两个小峰：一个与3'-氨基-3'-脱氧胸苷（AMT）共洗脱；另一个的保留时间根据该领域的出版物对应于3'-氨基-3'-脱氧胸苷葡糖醛酸苷。然而，进一步研究表明该化合物被表征为氚化水，可能代表AZT的分解代谢终产物。尽管葡糖醛酸化是所研究的四个物种中的主要代谢途径，但AZT在大鼠和狗肝细胞中的生物转化速率远低于猴子和人类肝细胞。最后，体内和体外代谢数据之间获得了极好的相关性。
