Hankins G D, Lowery C L, Scott R T, Morrow W R, Carey K D, Leland M M, Colvin E V
Wilford Hall USAF Medical Center/SGHO, Lackland AFB, TX 78236-5300.
Am J Obstet Gynecol. 1990 Sep;163(3):728-32. doi: 10.1016/0002-9378(90)91057-j.
Approximately one third of infants born to human immunodeficiency virus type 1 seropositive mothers have evidence of infection or of acquired immunodeficiency syndrome by the age of 18 months. One fifth of infected infants also have died by age 18 months. This prevalence, combined with the demonstration that zidovudine (formerly azidothymidine) can decrease mortality and the frequency of opportunistic infections in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome--related complex, may lead to increasing use of azidothymidine in pregnancy despite a paucity of information regarding its pharmacokinetics. To further investigate the distribution of azidothymidine and its inactive metabolite 5'-glucuronide azidothymidine in the mother, fetus, and amniotic fluid, 12 near-term pregnant baboons were given oral azidothymidine (21 mg/kg/day in four divided doses every 6 hours, equivalent to the usual nonpregnant human dose of 1500 mg/day). Specimens of maternal blood, fetal arterial blood obtained by percutaneous umbilical cord blood sampling, and amniotic fluid were obtained after from one to 17 doses of azidothymidine. Azidothymidine levels were measured by radioimmunoassay with the INCSTAR commercial radioimmunoassay kit and using Escherichia coli beta-glucuronidase for determination of 5'-glucuronide azidothymidine levels. Paired analyses revealed significant concentration gradients between amniotic fluid, fetal serum, and maternal serum for both azidothymidine (p less than 0.019) and 5'-glucuronide azidothymidine (p less than 0.002). The amniotic fluid 5'-glucuronide azidothymidine level increased with increasing doses of azidothymidine despite the fact that the maternal azidothymidine and 5'-glucuronide azidothymidine concentrations were unchanged. This accumulation of amniotic fluid 5'-glucuronide azidothymidine may provide a functional drug reservoir and contribute to the higher fetal concentrations of the medication and its metabolite. Alternatively, the higher fetal levels may represent slower clearance in the fetus than in the mother. Further studies appear warranted with respect to possible adverse fetal effects, especially bone marrow suppression with prolonged and chronic exposure to azidothymidine.
大约三分之一的1型人类免疫缺陷病毒血清反应阳性母亲所生婴儿在18个月龄时出现感染证据或获得性免疫缺陷综合征。五分之一的受感染婴儿在18个月龄时也已死亡。这种患病率，再加上齐多夫定（原叠氮胸苷）可降低获得性免疫缺陷综合征或与获得性免疫缺陷综合征相关综合征患者的死亡率和机会性感染频率的证明，可能导致孕期使用叠氮胸苷的情况增加，尽管关于其药代动力学的信息匮乏。为了进一步研究叠氮胸苷及其无活性代谢产物5'-葡萄糖醛酸叠氮胸苷在母体、胎儿和羊水中的分布，给12只近足月妊娠的狒狒口服叠氮胸苷（21mg/kg/天，分4次给药，每6小时1次，相当于非妊娠人类常用剂量1500mg/天）。在给予1至17剂叠氮胸苷后，采集母体血液、经皮脐血采样获得的胎儿动脉血和羊水样本。使用INCSTAR商用放射免疫分析试剂盒通过放射免疫分析测定叠氮胸苷水平，并使用大肠杆菌β-葡萄糖醛酸酶测定5'-葡萄糖醛酸叠氮胸苷水平。配对分析显示，羊水、胎儿血清和母体血清之间的叠氮胸苷（p<0.019）和5'-葡萄糖醛酸叠氮胸苷（p<0.002）浓度梯度均有显著差异。尽管母体叠氮胸苷和5'-葡萄糖醛酸叠氮胸苷浓度未变，但羊水5'-葡萄糖醛酸叠氮胸苷水平随叠氮胸苷剂量增加而升高。羊水5'-葡萄糖醛酸叠氮胸苷的这种蓄积可能提供一个功能性药物储存库，并导致胎儿体内药物及其代谢产物浓度更高。或者，胎儿体内较高的水平可能代表其清除速度比母体慢。关于可能的胎儿不良影响，尤其是长期和慢性接触叠氮胸苷导致的骨髓抑制，似乎有必要进行进一步研究。
