van sen Bongard H J G Desirée, Pluim Dick, Rosing Hilde, Nan-Offeringa Lianda, Schot Margaret, Ravic Miroslav, Schellens Jan H M, Beijnen Jos H
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, 1066 EC Amsterdam, The Netherlands.
Anticancer Drugs. 2002 Sep;13(8):807-14. doi: 10.1097/00001813-200209000-00004.
E7070 is a novel sulfonamide anticancer agent that arrests the G /S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1,000 mg) radiolabeled by (14)C in the benzene disulfonamide moiety (cohort 1, n = 6) or in the indole moiety (cohort 2, n = 7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography-tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration-time curve (AUC) based on radio-activity measurements (32.5 and 28.9 h. mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h x mmol/l) and M1 (0.1 h x mmol/l) in all patients. The excretion of radioactivity (mean +/- SD) as a percentage of administered radioactivity was higher in urine [63.7 +/- 9.8% (cohort 1) and 61.5 +/- 5.5% (cohort 2)] than in feces [22.7 +/- 2.6% (1) and 21.1 +/- 3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and fecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway.
E7070是一种新型磺胺类抗癌药物，可使细胞周期停滞于G/S期。临床前研究和I期研究已证明该药物的药代动力学呈非线性。本研究的目的是对癌症患者体内E7070及其代谢产物1,4-苯磺酰胺（M1）的排泄情况进行定量分析。将（14）C标记于苯二磺酰胺部分（队列1，n = 6）或吲哚部分（队列2，n = 7）的E7070（1000 mg）静脉输注1小时。通过液体闪烁计数法测定血浆、红细胞、尿液和粪便中的放射性水平，并通过液相色谱-串联质谱联用仪（LC/ESI-MS/MS）测定血浆、尿液和粪便中E7070和M1的浓度。在血浆中，基于放射性测量的浓度-时间曲线下面积（AUC）平均值（队列1和队列2分别为32.5和28.9 h·mmol/L）显著高于所有患者中E7070（3.8 h·mmol/L）和M1（0.1 h·mmol/L）的AUC平均值。在平均11天的收集期内，尿液中放射性排泄量（平均值±标准差）占给药放射性的百分比[队列1为63.7±9.8%，队列2为61.5±5.5%]高于粪便[队列1为22.7±2.6%，队列2为21.1±3.1%]。在两个队列中，E7070（分别为2.3%和2.7%）和M1（分别为5.3%和5.1%）的尿液和粪便回收率贡献较低。随后对尿液进行的在线放射性同位素检测的高效液相色谱分析表明，高放射性水平是由E7070和M1以外的化合物引起的。主要代谢产物是由E7070的羟基化代谢产物经葡萄糖醛酸化形成的。总之，E7070的苯磺酰胺和吲哚部分的排泄情况相同，经肾脏排泄的量高于经胃肠道排泄的量。E7070被广泛转化为目前尚未鉴定的代谢产物。葡萄糖醛酸化是主要的代谢途径。
