Souid A K, Fahey R C, Dubowy R L, Newton G L, Bernstein M L
State University of New York, Health Science Center at Syracuse, Department of Pediatrics, 750 East Adams Street, Syracuse, NY 13210, USA.
Cancer Chemother Pharmacol. 1999;44(6):498-504. doi: 10.1007/s002800051124.
Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna.
WR-2721 was administered (15 min intravenous infusion of 825 mg/m(2) per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence.
The active metabolite of the drug, WR-1065, peaked at 100 microM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half-life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at approximately 1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by approximately 50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being approximately 36%.
(1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of approximately 16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.
以往关于WR - 2721的人体药代动力学研究仅限于接受铂类化合物治疗患者的血浆水平，且均未涉及WR - 2721对内源性硫醇的影响。在本研究（儿童肿瘤学组研究编号9457）中，我们测定了接受大剂量烷化剂与美司钠联合治疗患者全血、血浆及血细胞中WR - 2721及其活性代谢产物以及半胱氨酸和谷胱甘肽的水平。
对5例接受异环磷酰胺和环磷酰胺联合美司钠治疗的转移性尤因肉瘤患者给予WR - 2721（每剂量825 mg/m²，静脉输注15分钟，共2剂）。在采血时用单溴联苯胺（mBBr）标记细胞内和细胞外血液中的硫醇，随后通过高效液相色谱法分离低分子量（LMW）硫醇并通过荧光检测。
药物的活性代谢产物WR - 1065在WR - 2721输注结束时在血浆和血细胞中的峰值为100 microM，并以快速的初始半衰期衰减。在WR - 2721输注后约1小时，血浆和血细胞中存在可检测水平的WR - 1065及其LMW二硫化物。在第一次WR - 2721输注结束时（美司钠输注前），血浆和血细胞中的平均半胱氨酸水平增加了一倍多，平均Cys - SS - LMW（胱氨酸和混合的LMW二硫化物）水平下降了约50%。在5例患者中的4例中，血细胞中的还原型谷胱甘肽水平在第一次WR - 2721输注结束时升高，平均增加约36%。
（1）WR - 1065由WR - 2721迅速形成并在血浆和血细胞之间达到平衡；（2）WR - 1065在血浆和血细胞中以相似的快速初始半衰期（约16分钟）衰减；（3）WR - 2721治疗可增加血浆和血细胞中的半胱氨酸，其作用与美司钠相似；（4）WR - 2721治疗似乎可增加血细胞中的谷胱甘肽水平；（5）美司钠对患者体内WR - 2721的转归没有实质性影响。
