Poirier M C, Patterson T A, Slikker W, Olivero O A
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
J Acquir Immune Defic Syndr. 1999 Dec 15;22(5):477-83. doi: 10.1097/00126334-199912150-00008.
In the United States, the nucleoside analogue drug 3'-azido-3'deoxythymidine (AZT; also called zidovudine or ZDV) is given to most pregnant women who produce a positive test result for HIV-1. To investigate transplacental distribution and genotoxicity of AZT, near-term pregnant rhesus (Macaca mulatta) monkeys and their fetuses were studied. Four pregnant monkeys were continuously infused with 8 mg AZT/kg body weight for the 4 hours just prior to hysterotomy at term. This short-term AZT exposure resulted in AZT incorporation into DNA of fetal liver, lung, heart, skeletal muscle, brain, testis, and placenta, which varied between 29 and 1944 molecules of AZT/10(6) nucleotides. In contrast, values for AZT and combined metabolites, determined by radioactivity, varied between 0.94 and 5.20 microg AZT equivalents/g tissue. A fifth animal, (H076), was infused with 17.3 mg AZT/kg body weight for approximately 3 hours, followed by 1 hour without drug before hysterotomy. Similar to the 4 other monkeys, variable levels of AZT (16-147 molecules of AZT/10(6) nucleotides) were incorporated into organ DNA of H076, whereas organ tissues contained less-variable levels of AZT and metabolites (0.86-2.05 microg AZT equivalents/g tissue). For H076, at hysterotomy 1 hour after discontinuation of drug, values for AZT and the 3'-azido-3'-deoxythymidine-beta-D-glucuronide (AZTG) in fetal blood and amniotic fluid were twofold and threefold higher than those in maternal blood. Most AZT pharmacokinetic parameters in the fifth monkey were similar to those previously reported for the first 4 monkeys and those observed in a similar study of pregnant women. These data show that a short-term AZT infusion in pregnant rhesus monkeys, which have similar AZT pharmacokinetics to those present in a pregnant human, results in incorporation of drug into the DNA of placenta and most fetal organs. Data imply that the human fetus may also be subject to incorporation of AZT into DNA even after short-term AZT infusion to the mother just before delivery.
在美国，对于大多数HIV-1检测呈阳性的孕妇，都会给予核苷类似物药物3'-叠氮-3'-脱氧胸苷（AZT；也称为齐多夫定或ZDV）。为了研究AZT的胎盘转运和遗传毒性，对接近足月的怀孕恒河猴（猕猴）及其胎儿进行了研究。4只怀孕的猴子在足月剖宫产术前4小时持续输注8毫克AZT/千克体重。这种短期的AZT暴露导致AZT掺入胎儿肝脏、肺、心脏、骨骼肌、大脑、睾丸和胎盘的DNA中，每10⁶个核苷酸中AZT的分子数在29至1944之间。相比之下，通过放射性测定的AZT及其代谢产物总和的值在0.94至5.20微克AZT当量/克组织之间。第五只动物（H076）输注了17.3毫克AZT/千克体重约3小时，然后在剖宫产术前1小时不使用药物。与其他4只猴子类似，H076的器官DNA中掺入了不同水平的AZT（每10⁶个核苷酸中16至147个AZT分子），而器官组织中AZT及其代谢产物的水平变化较小（0.86至2.05微克AZT当量/克组织）。对于H076，在停药1小时后进行剖宫产时，胎儿血液和羊水中的AZT及3'-叠氮-3'-脱氧胸苷-β-D-葡萄糖醛酸（AZTG）值分别比母体血液中的值高两倍和三倍。第五只猴子的大多数AZT药代动力学参数与之前报道的前4只猴子以及在一项类似的孕妇研究中观察到的参数相似。这些数据表明，在怀孕恒河猴中进行短期AZT输注，其AZT药代动力学与孕妇相似，会导致药物掺入胎盘和大多数胎儿器官的DNA中。数据表明，即使在分娩前对母亲进行短期AZT输注后，人类胎儿的DNA也可能会掺入AZT。
