Intravenous and oral zidovudine pharmacokinetics and coagulation effects in asymptomatic human immunodeficiency virus-infected hemophilia patients.
Intravenous and oral zidovudine pharmacokinetics and coagulation effects in asymptomatic human immunodeficiency virus-infected hemophilia patients.
复制标题
无症状人类免疫缺陷病毒感染的血友病患者静脉和口服齐多夫定的药代动力学和凝血作用。
DOI：
10.1128/aac.36.10.2245
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发表时间：
1992
影响因子：
4.9
通讯作者：
Reichman,RC
中科院分区：
文献类型：
--
作者：
Morse,GD;Portmore,AC;Marder,V;Plank,C;Olson,J;Taylor,C;Bonnez,W;Reichman,RC
对11例接受齐多夫定（ZDV）治疗的人类免疫缺陷病毒感染的无症状血友病患者进行了为期12周的药代动力学和凝血研究。患者在清醒时每4小时接受300 mg（本研究时接受的剂量）;连续24小时静脉内（i. v.）在第1、6和12周进行12小时口服药代动力学研究。在第0、4、8和12周进行凝血研究。记录在ZDV治疗前、治疗期间和治疗后12周期间输注的因子VIII和IX以及冷沉淀物的单位数。静脉注射和口服ZDV后，血浆中的浓度在前4小时内迅速下降，在一些患者中，在4至10小时仍可检测到ZDV。静脉总清除率（平均值+/-标准差）分别为14.9 +/- 7.3、11.2 +/- 3.7和15.1 +/- 4.7 ml/min/kg体重。静脉内分布体积分别为1.08 +/- 0.5、1.0 +/- 0.4和1.65 +/- 1.4升/千克。第1、6和12周的生物利用度分别为0.54 +/- 0.22、0.46 +/- 0.19和0.59 +/- 0.13。ZDV-葡糖苷酸（GZDV）的分布模式与ZDV相似，经口给药后血浆GZDV/ZDV比值峰值较高，与首过代谢一致。在某些个体中，高达33%的静脉注射剂量以原型排泄。在第6周和第12周，在一些患者的尿液中回收了大于300 mg的总ZDV（GZDV加ZDV），表明组织再分布。口服ZDV给药后的血浆浓度在患者内和患者间均不同。在整个研究期间，血管性血友病抗原水平持续下降，但未伴随瑞斯托康辅助因子A活性的平行变化，也未观察到对凝血的临床不良影响。本研究表明，ZDV可用于血友病患者，而不会加重其出血倾向。ZDV清除率降低和ZDV终末消除相延长的临床意义需要在接受慢性ZDV治疗的患者中进行进一步研究。
Pharmacokinetic and coagulation studies were carried out over a 12-week period with 11 asymptomatic hemophilia patients with human immunodeficiency virus infection receiving zidovudine (ZDV). The patients received 300 mg every 4 h while awake (the accepted dose at the time of this study); consecutive 24-h intravenous (i.v.) and 12-h oral pharmacokinetic studies were conducted at weeks 1, 6, and 12. Coagulation studies were conducted at weeks 0, 4, 8, and 12. The numbers of units of factors VIII and IX and cryoprecipitate transfused during the 12-week periods before, during, and after ZDV treatment were recorded. Following i.v. and oral ZDV administration, the concentration in plasma declined rapidly over the first 4 h, and in some patients, ZDV was still detectable at 4 to 10 h. The i.v. total clearances (means +/- standard deviations) were 14.9 +/- 7.3, 11.2 +/- 3.7, and 15.1 +/- 4.7 ml/min/kg of body weight. The i.v. distribution volumes were 1.08 +/- 0.5, 1.0 +/- 0.4, and 1.65 +/- 1.4 liters/kg. The bioavailabilities were 0.54 +/- 0.22, 0.46 +/- 0.19, and 0.59 +/- 0.13 at weeks 1, 6, and 12, respectively. The pattern of ZDV-glucuronide (GZDV) disposition was similar to that of ZDV, and the peak plasma GZDV-to-ZDV ratio was higher after oral dosing, consistent with first-pass metabolism. In some individuals, up to 33% of an i.v. dose was excreted unchanged. At weeks 6 and 12, greater than 300 mg of total ZDV (GZDV plus ZDV) was recovered in the urine of some patients, suggesting tissue redistribution. Concentration in plasma after oral ZDV administration were variable, both within and between patients. The von Willebrand antigen level consistently decreased throughout the study but was not accompanied by a parallel change in ristocetin cofactor A activity, and no clinical adverse effects on coagulation were noted. This study demonstrates that ZDV can be used in hemophilia patients without worsening of their bleeding tendencies. The clinical significance of decreased ZDV clearance and the prolonged terminal elimination phase of ZDV will require further study with patients receiving chronic ZDV.