Cretton-Scott E, Placidi L, McClure H, Anderson D C, Sommadossi J P
Department of Pharmacology, University of Alabama at Birmingham, 35294, USA.
Cancer Chemother Pharmacol. 1996;38(2):117-22. doi: 10.1007/s002800050458.
The metabolic disposition and pharmacokinetics of TNP-470 were investigated in rhesus monkeys following intravenous administration of 5 mg/kg of [3H]-TNP-470. Rapid and extensive metabolism of parent drug to six metabolites occurred as demonstrated by the absence of unchanged drug in plasma and urine at time points as early as 6 min after administration. Substantial, yet variable, plasma levels of M-IV were detected in all three monkeys with a mean Cmax value of 3.54 microM. Five other metabolites, labeled M-I, M-II, M-III, M-V and M-VI, were also detected in biological fluids of monkeys. M-II, M-V and M-VI exhibited similar kinetic profiles with apparent plasma elimination half-life values of 0.91 +/- 0.37, 2.42 +/- 0.13 and 1.19 +/- 0.29 h respectively. In contrast, M-I, M-III and M-IV exhibited much shorter apparent plasma half-life values of 30 min or less. Urinary recovery within 36 h represented only 19.90 +/- 6.09% of the total administered dose. No radioactivity was detected beyond 36 h and during a 15-day sample collection period, suggesting that nonrenal (biliary) elimination of TNP-470 metabolites is a predominant excretion route in nonhuman primates. This study provides the first detailed in vivo analysis of TNP-470 metabolism and disposition using an animal model highly predictive of humans, consistent with the detection of the same TNP-470 metabolites in human tissues. A detailed understanding of TNP-470 metabolism and disposition is critical to fully elucidate the pharmacodynamic properties of this new anticancer drug as clinical investigations proceed.
在恒河猴静脉注射5mg/kg的[³H]-TNP-470后，对TNP-470的代谢分布和药代动力学进行了研究。母体药物迅速且广泛地代谢为六种代谢产物，给药后6分钟时血浆和尿液中就未检测到未代谢的药物，这证明了这一点。在所有三只猴子中均检测到了较高但有变化的M-IV血浆水平，平均Cmax值为3.54μM。在猴子的生物体液中还检测到了其他五种代谢产物，分别标记为M-I、M-II、M-III、M-V和M-VI。M-II、M-V和M-VI表现出相似的动力学特征，其表观血浆消除半衰期值分别为0.91±0.37、2.42±0.13和1.19±0.29小时。相比之下，M-I、M-III和M-IV的表观血浆半衰期值则短得多，为30分钟或更短。36小时内尿液回收量仅占总给药剂量的19.90±6.09%。在36小时后以及15天的样本采集期内均未检测到放射性，这表明TNP-470代谢产物的非肾（胆汁）消除是非人灵长类动物的主要排泄途径。本研究首次使用高度预测人类情况的动物模型对TNP-470的代谢和分布进行了详细的体内分析，这与在人体组织中检测到相同的TNP-470代谢产物一致。随着临床研究的推进，详细了解TNP-470的代谢和分布对于充分阐明这种新型抗癌药物的药效学特性至关重要。
